The ménage à trois of autophagy, lipid droplets and liver disease

References

• Antonioli M, Di Rienzo M, Piacentini M, et al. Emerging mechanisms in initiating and terminating autophagy. Trends Biochem Sci. 2017;42(1):28–41. .
   PubMed Web of Science ®Google Scholar
• Yu L, Chen Y, Tooze SA. Autophagy pathway: Cellular and molecular mechanisms. Autophagy. 2018;14(2):207–215.
   PubMed Web of Science ®Google Scholar
• Mizushima N, Yoshimori T, Ohsumi Y. The role of Atg proteins in autophagosome formation. Annu Rev Cell Dev Biol. 2011;27(1):107–132.
   PubMed Web of Science ®Google Scholar
• Klionsky DJ, Schulman BA. Dynamic regulation of macroautophagy by distinctive ubiquitin-like proteins. Nat Struct Mol Biol. 2014;21(4):336–345.
   PubMed Web of Science ®Google Scholar
• Tsukada M, Ohsumi Y. Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Lett. 1993;333(1–2):169–174.
   PubMed Web of Science ®Google Scholar
• Thumm M, Egner R, Koch B, et al. Isolation of autophagocytosis mutants of Saccharomyces cerevisiae. FEBS Lett. 1994;349(2):275–280. .
   PubMed Web of Science ®Google Scholar
• Harding TM, Morano KA, Scott SV, et al. Isolation and characterization of yeast mutants in the cytoplasm to vacuole protein targeting pathway. J Cell Biol. 1995;131(3):591–602. .
   PubMed Web of Science ®Google Scholar
• Wong PM, Puente C, Ganley IG, et al. The ULK1 complex: sensing nutrient signals for autophagy activation. Autophagy. 2013;9(2):124–137. .
   PubMed Web of Science ®Google Scholar
• Hosokawa N, Hara T, Kaizuka T, et al. Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol Biol Cell. 2009;20(7):1981–1991. .
   PubMed Web of Science ®Google Scholar
• Nazio F, Cecconi F. mTOR, AMBRA1, and autophagy: an intricate relationship. Cell Cycle. 2013;12(16):2524–2525.
   PubMed Web of Science ®Google Scholar
• Jung CH, Jun CB, Ro SH, et al. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell. 2009;20(7):1992–2003. .
   PubMed Web of Science ®Google Scholar
• Axe EL, Walker SA, Manifava M, et al. Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J Cell Biol. 2008;182(4):685–701. .
   PubMed Web of Science ®Google Scholar
• Roberts R, Ktistakis NT. Omegasomes: PI3P platforms that manufacture autophagosomes. Essays Biochem. 2013;55:17–27.
   PubMed Web of Science ®Google Scholar
• He C, Levine B. The Beclin 1 interactome. Curr Opin Cell Biol. 2010;22(2):140–149.
   PubMed Web of Science ®Google Scholar
• Mercer TJ, Gubas A, Tooze SA. A molecular perspective of mammalian autophagosome biogenesis. J Biol Chem. 2018;293(15):5386–5395.
   PubMed Web of Science ®Google Scholar
• Bakula D, Muller AJ, Zuleger T, et al. WIPI3 and WIPI4 beta-propellers are scaffolds for LKB1-AMPK-TSC signalling circuits in the control of autophagy. Nat Commun. 2017;8(1):15637. .
   PubMed Web of Science ®Google Scholar
• Proikas-Cezanne T, Takacs Z, Donnes P, et al. WIPI proteins: essential PtdIns3P effectors at the nascent autophagosome. J Cell Sci. 2015;128(2):207–217. .
   PubMed Web of Science ®Google Scholar
• Dooley HC, Razi M, Polson HE, et al. WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting Atg12-5-16L1. Mol Cell. 2014;55(2):238–252. .
   PubMed Web of Science ®Google Scholar
• Behrends C, Sowa ME, Gygi SP, et al. Network organization of the human autophagy system. Nature. 2010;466(7302):68–76. .
   PubMed Web of Science ®Google Scholar
• Galluzzi L, Baehrecke EH, Ballabio A, et al. Molecular definitions of autophagy and related processes. Embo J. 2017;36(13):1811–1836. .
   PubMed Web of Science ®Google Scholar
• Gatica D, Lahiri V, Klionsky DJ. Cargo recognition and degradation by selective autophagy. Nat Cell Biol. 2018;20(3):233–242.
   PubMed Web of Science ®Google Scholar
• Kirkin V, Rogov VV. A diversity of selective autophagy receptors determines the specificity of the autophagy pathway. Mol Cell. 2019;76(2):268–285.
   PubMed Web of Science ®Google Scholar
• Farre JC, Subramani S. Mechanistic insights into selective autophagy pathways: lessons from yeast. Nat Rev Mol Cell Biol. 2016;17(9):537–552.
   PubMed Web of Science ®Google Scholar
• Seo AY, Lau PW, Feliciano D, et al. AMPK and vacuole-associated Atg14p orchestrate mu-lipophagy for energy production and long-term survival under glucose starvation. Elife. 2017;6:e21690.
   PubMed Web of Science ®Google Scholar
• Roberts P, Moshitch-Moshkovitz S, Kvam E, et al. Piecemeal microautophagy of nucleus in Saccharomyces cerevisiae. Mol Biol Cell. 2003;14(1):129–141. .
   PubMed Web of Science ®Google Scholar
• Lemasters JJ. Variants of mitochondrial autophagy: types 1 and 2 mitophagy and micromitophagy (Type 3). Redox Biol. 2014;2:749–754.
   PubMed Web of Science ®Google Scholar
• Tekirdag K, Cuervo AM. Chaperone-mediated autophagy and endosomal microautophagy: joint by a chaperone. J Biol Chem. 2018;293(15):5414–5424.
   PubMed Web of Science ®Google Scholar
• Oku M, Sakai Y. Three distinct types of microautophagy based on membrane dynamics and molecular machineries. Bioessays. 2018;40(6):e1800008.
   PubMed Web of Science ®Google Scholar
• Sahu R, Kaushik S, Clement CC, et al. Microautophagy of cytosolic proteins by late endosomes. Dev Cell. 2011;20(1):131–139. .
   PubMed Web of Science ®Google Scholar
• Mejlvang J, Olsvik H, Svenning S, et al. Starvation induces rapid degradation of selective autophagy receptors by endosomal microautophagy. J Cell Biol. 2018;217(10):3640–3655. .
   PubMed Web of Science ®Google Scholar
• Kaushik S, Cuervo AM. Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends Cell Biol. 2012;22(8):407–417.
   PubMed Web of Science ®Google Scholar
• Dice JF. Peptide sequences that target cytosolic proteins for lysosomal proteolysis. Trends Biochem Sci. 1990;15(8):305–309.
   PubMed Web of Science ®Google Scholar
• Kaushik S, Cuervo AM. The coming of age of chaperone-mediated autophagy. Nat Rev Mol Cell Biol. 2018;19(6):365–381.
   PubMed Web of Science ®Google Scholar
• Cuervo AM, Dice JF. A receptor for the selective uptake and degradation of proteins by lysosomes. Science. 1996;273(5274):501–503.
   PubMed Web of Science ®Google Scholar
• Bandyopadhyay U, Kaushik S, Varticovski L, et al. The chaperone-mediated autophagy receptor organizes in dynamic protein complexes at the lysosomal membrane. Mol Cell Biol. 2008;28(18):5747–5763. .
   PubMed Web of Science ®Google Scholar
• Cuervo AM, Dice JF, Knecht E. A population of rat liver lysosomes responsible for the selective uptake and degradation of cytosolic proteins. J Biol Chem. 1997;272(9):5606–5615.
   PubMed Web of Science ®Google Scholar
• Martin S, Parton RG. Lipid droplets: a unified view of a dynamic organelle. Nat Rev Mol Cell Biol. 2006;7(5):373–378.
   PubMed Web of Science ®Google Scholar
• Olzmann JA, Carvalho P. Dynamics and functions of lipid droplets. Nat Rev Mol Cell Biol. 2019;20(3):137–155.
   PubMed Web of Science ®Google Scholar
• Ward C, Martinez-Lopez N, Otten EG, et al. Autophagy, lipophagy and lysosomal lipid storage disorders. Biochim Biophys Acta. 2016;1861:269–284.
   PubMed Web of Science ®Google Scholar
• Weidberg H, Shvets E, Elazar Z. Lipophagy: selective catabolism designed for lipids. Dev Cell. 2009;16(5):628–630.
   PubMed Web of Science ®Google Scholar
• Ma Y, Zhou Y, Zhu YC, et al. Lipophagy contributes to testosterone biosynthesis in male rat Leydig cells. Endocrinology. 2018;159(2):1119–1129. .
   PubMed Web of Science ®Google Scholar
• Cui W, Sathyanarayan A, Lopresti M, et al. Lipophagy-derived fatty acids undergo extracellular efflux via lysosomal exocytosis. Autophagy. 2020;19:1–16.
   Google Scholar
• Riffelmacher T, Clarke A, Richter FC, et al. Autophagy-dependent generation of free fatty acids is critical for normal neutrophil differentiation. Immunity 2017;47(3):466–480 e5. .
   PubMed Web of Science ®Google Scholar
• Folick A, Oakley HD, Yu Y, et al. Aging. lysosomal signaling molecules regulate longevity in Caenorhabditis elegans. Science. 2015;347:(6217):83–86. .
   PubMed Web of Science ®Google Scholar
• Natarajan SK, Rasineni K, Ganesan M, et al. Structure, function and metabolism of hepatic and adipose tissue lipid droplets: implications in alcoholic liver disease. Curr Mol Pharmacol. 2017;10(3):237–248. .
   PubMed Web of Science ®Google Scholar
• Itabe H, Yamaguchi T, Nimura S, et al. Perilipins: a diversity of intracellular lipid droplet proteins. Lipids Health Dis. 2017;16(1):83. .
   PubMedGoogle Scholar
• Trevino MB, Mazur-Hart D, Machida Y, et al. Liver perilipin 5 expression worsens hepatosteatosis but not insulin resistance in high fat-fed mice. Mol Endocrinol. 2015;29(10):1414–1425. .
   PubMedGoogle Scholar
• Zhang E, Cui W, Lopresti M, et al. Hepatic PLIN5 signals via SIRT1 to promote autophagy and prevent inflammation during fasting. J Lipid Res. 2020;61(3):338–350. .
   PubMed Web of Science ®Google Scholar
• Kaushik S, Cuervo AM. Degradation of lipid droplet-associated proteins by chaperone-mediated autophagy facilitates lipolysis. Nat Cell Biol. 2015;17(6):759–770.
   PubMed Web of Science ®Google Scholar
• Bolsoni-Lopes A, Alonso-Vale MI. Lipolysis and lipases in white adipose tissue - An update. Arch Endocrinol Metab. 2015;59(4):335–342.
   PubMed Web of Science ®Google Scholar
• Dupont N, Chauhan S, Arko-Mensah J, et al. Neutral lipid stores and lipase PNPLA5 contribute to autophagosome biogenesis. Curr Biol. 2014;24(6):609–620. .
   PubMed Web of Science ®Google Scholar
• Velikkakath AK, Nishimura T, Oita E, et al. Mammalian Atg2 proteins are essential for autophagosome formation and important for regulation of size and distribution of lipid droplets. Mol Biol Cell. 2012;23(5):896–909. .
   PubMed Web of Science ®Google Scholar
• Shibata M, Yoshimura K, Furuya N, et al. The MAP1-LC3 conjugation system is involved in lipid droplet formation. Biochem Biophys Res Commun. 2009;382(2):419–423. .
   PubMed Web of Science ®Google Scholar
• Pfisterer SG, Bakula D, Frickey T, et al. Lipid droplet and early autophagosomal membrane targeting of Atg2A and Atg14L in human tumor cells. J Lipid Res. 2014;55(7):1267–1278. .
   PubMed Web of Science ®Google Scholar
• Takeuchi K, Reue K. Biochemistry, physiology, and genetics of GPAT, AGPAT, and lipin enzymes in triglyceride synthesis. Am J Physiol Endocrinol Metab. 2009;296(6):E1195–209.
   PubMed Web of Science ®Google Scholar
• Shi Y, Cheng D. Beyond triglyceride synthesis: the dynamic functional roles of MGAT and DGAT enzymes in energy metabolism. Am J Physiol Endocrinol Metab. 2009;297(1):E10–8.
   PubMed Web of Science ®Google Scholar
• Yu J, Loh K, Song ZY, et al. Update on glycerol-3-phosphate acyltransferases: the roles in the development of insulin resistance. Nutr Diabetes. 2018;8(1):34. .
   PubMedGoogle Scholar
• Thiam AR, Foret L. The physics of lipid droplet nucleation, growth and budding. Biochim Biophys Acta. 2016;1861(8):715–722.
   PubMed Web of Science ®Google Scholar
• Jacquier N, Choudhary V, Mari M, et al. Lipid droplets are functionally connected to the endoplasmic reticulum in Saccharomyces cerevisiae [Research Support, Non-U.S. Gov’t]. J Cell Sci. 2011;124(14):2424–2437. .
   PubMed Web of Science ®Google Scholar
• Kassan A, Herms A, Fernandez-Vidal A, et al. Acyl-CoA synthetase 3 promotes lipid droplet biogenesis in ER microdomains. J Cell Biol. 2013;203(6):985–1001. .
   PubMed Web of Science ®Google Scholar
• Ben M’barek K, Ajjaji D, Chorlay A, et al. ER membrane phospholipids and surface tension control cellular lipid droplet formation. Dev Cell. 2017;41(6):591–604 e7. .
   PubMed Web of Science ®Google Scholar
• Gao M, Huang X, Song BL, et al. The biogenesis of lipid droplets: Lipids take center stage. Prog Lipid Res. 2019;75:100989.
   PubMed Web of Science ®Google Scholar
• Becuwe M, Bond LM, Pinto AFM, et al. FIT2 is an acyl-coenzyme A diphosphatase crucial for endoplasmic reticulum homeostasis. J Cell Biol. 2020Oct5 219;(10)e202006111.
   PubMed Web of Science ®Google Scholar
• Choudhary V, Golani G, Joshi AS, et al. Architecture of lipid droplets in endoplasmic reticulum is determined by phospholipid intrinsic curvature. Curr Biol. 2018;28(6):915–926 e9. .
   PubMed Web of Science ®Google Scholar
• Yan R, Qian H, Lukmantara I, et al. Human SEIPIN binds anionic phospholipids. Dev Cell. 2018;47(2):248–256 e4. .
   PubMed Web of Science ®Google Scholar
• Fei W, Shui G, Gaeta B, et al. Fld1p, a functional homologue of human seipin, regulates the size of lipid droplets in yeast. J Cell Biol. 2008;180(3):473–482. .
   PubMed Web of Science ®Google Scholar
• Szymanski KM, Binns D, Bartz R, et al. The lipodystrophy protein seipin is found at endoplasmic reticulum lipid droplet junctions and is important for droplet morphology. Proc Natl Acad Sci U S A. 2007;104(52):20890–20895.
   PubMed Web of Science ®Google Scholar
• Wang H, Becuwe M, Housden BE, et al. Seipin is required for converting nascent to mature lipid droplets. Elife 2016;5:e16582.
   PubMed Web of Science ®Google Scholar
• Wilfling F, Wang H, Haas JT, et al. Triacylglycerol synthesis enzymes mediate lipid droplet growth by relocalizing from the ER to lipid droplets. Dev Cell. 2013;24(4):384–399. .
   PubMed Web of Science ®Google Scholar
• Choudhary V, Ojha N, Golden A, et al. A conserved family of proteins facilitates nascent lipid droplet budding from the ER. J Cell Biol. 2015;211(2):261–271. .
   PubMed Web of Science ®Google Scholar
• Walther TC, Chung J, Farese RV Jr. Lipid droplet biogenesis. Annu Rev Cell Dev Biol. 2017;33(1):491–510.
   PubMedGoogle Scholar
• Zechner R, Zimmermann R, Eichmann TO, et al. FAT SIGNALS–lipases and lipolysis in lipid metabolism and signaling. Cell Metab. 2012;15(3):279–291. .
   PubMed Web of Science ®Google Scholar
• Rambold AS, Cohen S, Lippincott-Schwartz J. Fatty acid trafficking in starved cells: regulation by lipid droplet lipolysis, autophagy, and mitochondrial fusion dynamics. Dev Cell. 2015;32(6):678–692.
   PubMed Web of Science ®Google Scholar
• Zehmer JK, Huang Y, Peng G, et al. A role for lipid droplets in inter-membrane lipid traffic. Proteomics. 2009;9(4):914–921. .
   PubMed Web of Science ®Google Scholar
• Dirkx R, Vanhorebeek I, Martens K, et al. Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities. Hepatology. 2005;41(4):868–878. .
   PubMed Web of Science ®Google Scholar
• Binns D, Januszewski T, Chen Y, et al. An intimate collaboration between peroxisomes and lipid bodies. J Cell Biol. 2006;173(5):719–731. .
   PubMed Web of Science ®Google Scholar
• Zhang H, Wang Y, Li J, et al. Proteome of skeletal muscle lipid droplet reveals association with mitochondria and apolipoprotein a-I. J Proteome Res. 2011;10(10):4757–4768. .
   PubMed Web of Science ®Google Scholar
• Wang H, Sreenivasan U, Gong DW, et al. Cardiomyocyte-specific perilipin 5 overexpression leads to myocardial steatosis and modest cardiac dysfunction. J Lipid Res. 2013;54(4):953–965. .
   PubMed Web of Science ®Google Scholar
• Shpilka T, Welter E, Borovsky N, et al. Lipid droplets and their component triglycerides and steryl esters regulate autophagosome biogenesis. Embo J. 2015;34(16):2117–2131. .
   PubMed Web of Science ®Google Scholar
• Ogasawara Y, Cheng J, Tatematsu T, et al. Long-term autophagy is sustained by activation of CCTbeta3 on lipid droplets. Nat Commun. 2020;11(1):4480. .
   PubMed Web of Science ®Google Scholar
• Wang CW. Lipid droplets, lipophagy, and beyond. Biochim Biophys Acta. 2016;1861(8):793–805.
   PubMed Web of Science ®Google Scholar
• Zechner R, Madeo F, Kratky D. Cytosolic lipolysis and lipophagy: two sides of the same coin. Nat Rev Mol Cell Biol. 2017;18(11):671–684.
   PubMed Web of Science ®Google Scholar
• Singh R, Kaushik S, Wang Y, et al. Autophagy regulates lipid metabolism. Nature. 2009;458(7242):1131–1135. .
   PubMed Web of Science ®Google Scholar
• Van Zutphen T, Todde V, De Boer R, et al. Lipid droplet autophagy in the yeast Saccharomyces cerevisiae. Mol Biol Cell. 2014;25(2):290–301. .
   PubMed Web of Science ®Google Scholar
• Ouimet M, Franklin V, Mak E, et al. Autophagy regulates cholesterol efflux from macrophage foam cells via lysosomal acid lipase. Cell Metab. 2011;13(6):655–667. .
   PubMed Web of Science ®Google Scholar
• Kaushik S, Arias E, Kwon H, et al. Loss of autophagy in hypothalamic POMC neurons impairs lipolysis. EMBO Rep. 2012;13(3):258–265. .
   PubMed Web of Science ®Google Scholar
• Khaldoun SA, Emond-Boisjoly MA, Chateau D, et al. Autophagosomes contribute to intracellular lipid distribution in enterocytes. Mol Biol Cell. 2014;25(1):118–132. .
   PubMed Web of Science ®Google Scholar
• Cairo M, Villarroya J, Cereijo R, et al. Thermogenic activation represses autophagy in brown adipose tissue. Int J Obes (Lond). 2016;40(10):1591–1599. .
   PubMed Web of Science ®Google Scholar
• Martinez-Lopez N, Garcia-Macia M, Sahu S, et al. Autophagy in the CNS and periphery coordinate lipophagy and lipolysis in the brown adipose tissue and liver. Cell Metab. 2016;23(1):113–127. .
   PubMed Web of Science ®Google Scholar
• Lam T, Harmancey R, Vasquez H, et al. Reversal of intramyocellular lipid accumulation by lipophagy and a p62-mediated pathway. Cell Death Discov. 2016;2(1):16061. .
   PubMedGoogle Scholar
• Minami S, Yamamoto T, Takabatake Y, et al. Lipophagy maintains energy homeostasis in the kidney proximal tubule during prolonged starvation. Autophagy. 2017;13(10):1629–1647. .
   PubMed Web of Science ®Google Scholar
• Miceli C, Roccio F, Penalva-Mousset L, et al. The primary cilium and lipophagy translate mechanical forces to direct metabolic adaptation of kidney epithelial cells. Nat Cell Biol. 2020;22(9):1091–1102. .
   PubMed Web of Science ®Google Scholar
• Kaini RR, Sillerud LO, Zhaorigetu S, et al. Autophagy regulates lipolysis and cell survival through lipid droplet degradation in androgen-sensitive prostate cancer cells. Prostate. 2012;72(13):1412–1422. .
   PubMed Web of Science ®Google Scholar
• Schott MB, Weller SG, Schulze RJ, et al. Lipid droplet size directs lipolysis and lipophagy catabolism in hepatocytes. J Cell Biol. 2019;218(10):3320–3335. .
   PubMed Web of Science ®Google Scholar
• Spandl J, Lohmann D, Kuerschner L, et al. Ancient ubiquitous protein 1 (AUP1) localizes to lipid droplets and binds the E2 ubiquitin conjugase G2 (Ube2g2) via its G2 binding region. J Biol Chem. 2011;286(7):5599–5606. .
   PubMed Web of Science ®Google Scholar
• Zhang J, Lan Y, Li MY, et al. Flaviviruses exploit the lipid droplet protein AUP1 to trigger lipophagy and drive virus production. Cell Host Microbe. 2018;23(6):819–831 e5. .
   PubMed Web of Science ®Google Scholar
• Eastman SW, Yassaee M, Bieniasz PD. A role for ubiquitin ligases and Spartin/SPG20 in lipid droplet turnover. J Cell Biol. 2009;184(6):881–894.
   PubMed Web of Science ®Google Scholar
• Hooper C, Puttamadappa SS, Loring Z, et al. Spartin activates atrophin-1-interacting protein 4 (AIP4) E3 ubiquitin ligase and promotes ubiquitination of adipophilin on lipid droplets. BMC Biol. 2010;8(1):72. .
   PubMedGoogle Scholar
• Tsai TH, Chen E, Li L, et al. The constitutive lipid droplet protein PLIN2 regulates autophagy in liver. Autophagy. 2017;13(7):1130–1144. .
   PubMed Web of Science ®Google Scholar
• Wang L, Zhou J, Yan S, et al. Ethanol-triggered lipophagy requires SQSTM1 in AML12 hepatic cells. Sci Rep. 2017;7(1):12307. .
   PubMedGoogle Scholar
• Ding WX, Li M, Chen X, et al. Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice. Gastroenterology. 2010;139(5):1740–1752. .
   PubMed Web of Science ®Google Scholar
• Yan Y, Wang H, Wei C, et al. HDAC6 regulates lipid droplet turnover in response to nutrient deprivation via p62-mediated selective autophagy. J Genet Genomics. 2019;46(4):221–229. .
   PubMed Web of Science ®Google Scholar
• Johnston JA, Ward CL, Kopito RR. Aggresomes: a cellular response to misfolded proteins. J Cell Biol. 1998;143(7):1883–1898.
   PubMed Web of Science ®Google Scholar
• Iwata A, Riley BE, Johnston JA, et al. HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin. J Biol Chem. 2005;280(48):40282–40292. .
   PubMed Web of Science ®Google Scholar
• Boyault C, Zhang Y, Fritah S, et al. HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregates. Genes Dev. 2007;21(17):2172–2181. .
   PubMed Web of Science ®Google Scholar
• Rui YN, Xu Z, Patel B, et al. Huntingtin functions as a scaffold for selective macroautophagy. Nat Cell Biol. 2015;17(3):262–275. .
   PubMed Web of Science ®Google Scholar
• Sathyanarayan A, Mashek MT, Mashek DG. ATGL promotes autophagy/lipophagy via SIRT1 to control hepatic lipid droplet catabolism. Cell Rep. 2017;19(1):1–9.
   PubMed Web of Science ®Google Scholar
• Lee IH, Cao L, Mostoslavsky R, et al. A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc Natl Acad Sci U S A. 2008;105(9):3374–3379. .
   PubMed Web of Science ®Google Scholar
• Stenmark H. Rab GTPases as coordinators of vesicle traffic. Nat Rev Mol Cell Biol. 2009;10(8):513–525.
   PubMed Web of Science ®Google Scholar
• Vitelli R, Santillo M, Lattero D, et al. Role of the small GTPase Rab7 in the late endocytic pathway. J Biol Chem. 1997;272(7):4391–4397. .
   PubMed Web of Science ®Google Scholar
• Gutierrez MG, Munafo DB, Beron W, et al. Rab7 is required for the normal progression of the autophagic pathway in mammalian cells. J Cell Sci. 2004;117(13):2687–2697. .
   PubMed Web of Science ®Google Scholar
• Jager S, Bucci C, Tanida I, et al. Role for Rab7 in maturation of late autophagic vacuoles. J Cell Sci. 2004;117(20):4837–4848. .
   PubMed Web of Science ®Google Scholar
• Schroeder B, Schulze RJ, Weller SG, et al. The small GTPase Rab7 as a central regulator of hepatocellular lipophagy. Hepatology. 2015;61(6):1896–1907. .
   PubMed Web of Science ®Google Scholar
• Lizaso A, Tan KT, Lee YH. beta-adrenergic receptor-stimulated lipolysis requires the RAB7-mediated autolysosomal lipid degradation. Autophagy. 2013;9(8):1228–1243.
   PubMed Web of Science ®Google Scholar
• Li Z, Schulze RJ, Weller SG, et al. A novel Rab10-EHBP1-EHD2 complex essential for the autophagic engulfment of lipid droplets. Sci Adv. 2016;2(12):e1601470. .
   PubMed Web of Science ®Google Scholar
• Sinha RA, You SH, Zhou J, et al. Thyroid hormone stimulates hepatic lipid catabolism via activation of autophagy. J Clin Invest. 2012;122(7):2428–2438. .
   PubMed Web of Science ®Google Scholar
• Byun S, Seok S, Kim YC, et al. Fasting-induced FGF21 signaling activates hepatic autophagy and lipid degradation via JMJD3 histone demethylase. Nat Commun. 2020;11(1):807. .
   PubMed Web of Science ®Google Scholar
• Gao Y, Zhang W, Zeng LQ, et al. Exercise and dietary intervention ameliorate high-fat diet-induced NAFLD and liver aging by inducing lipophagy. Redox Biol. 2020;36:101635.
   PubMed Web of Science ®Google Scholar
• Kim J, Kundu M, Viollet B, et al. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol. 2011;13(2):132–141. .
   PubMed Web of Science ®Google Scholar
• Kim J, Kim YC, Fang C, et al. Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy. Cell. 2013;152(1–2):290–303. .
   PubMed Web of Science ®Google Scholar
• Canto C, Gerhart-Hines Z, Feige JN, et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature. 2009;458(7241):1056–1060. .
   PubMed Web of Science ®Google Scholar
• Raben N, Puertollano R. TFEB and TFE3: linking lysosomes to cellular adaptation to stress. Annu Rev Cell Dev Biol. 2016;32(1):255–278.
   PubMedGoogle Scholar
• Napolitano G, Ballabio A. TFEB at a glance. J Cell Sci. 2016;129(13):2475–2481.
   PubMed Web of Science ®Google Scholar
• Settembre C, De Cegli R, Mansueto G, et al. TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. Nat Cell Biol. 2013;15(6):647–658. .
   PubMed Web of Science ®Google Scholar
• Xiong J, Wang K, He J, et al. TFE3 alleviates hepatic steatosis through autophagy-induced lipophagy and PGC1alpha-mediated fatty acid beta-oxidation. Int J Mol Sci. 2016;17(3):387. .
   PubMed Web of Science ®Google Scholar
• Chakrabarti P, Kandror KV. FoxO1 controls insulin-dependent adipose triglyceride lipase (ATGL) expression and lipolysis in adipocytes. J Biol Chem. 2009;284(20):13296–13300.
   PubMed Web of Science ®Google Scholar
• Lettieri Barbato D, Tatulli G, Aquilano K, et al. FoxO1 controls lysosomal acid lipase in adipocytes: implication of lipophagy during nutrient restriction and metformin treatment. Cell Death Dis. 2013;4(10):e861. .
   PubMedGoogle Scholar
• Tao R, Wei D, Gao H, et al. Hepatic FoxOs regulate lipid metabolism via modulation of expression of the nicotinamide phosphoribosyltransferase gene. J Biol Chem. 2011;286(16):14681–14690. .
   PubMed Web of Science ®Google Scholar
• Xiong X, Tao R, DePinho RA, et al. The autophagy-related gene 14 (Atg14) is regulated by forkhead box O transcription factors and circadian rhythms and plays a critical role in hepatic autophagy and lipid metabolism. J Biol Chem. 2012;287(46):39107–39114. .
   PubMed Web of Science ®Google Scholar
• Seok S, Fu T, Choi SE, et al. Transcriptional regulation of autophagy by an FXR-CREB axis. Nature. 2014;516(7529):108–111. .
   PubMed Web of Science ®Google Scholar
• Lee JM, Wagner M, Xiao R, et al. Nutrient-sensing nuclear receptors coordinate autophagy. Nature. 2014;516(7529):112–115. .
   PubMed Web of Science ®Google Scholar
• Vevea JD, Garcia EJ, Chan RB, et al. Role for lipid droplet biogenesis and microlipophagy in adaptation to lipid imbalance in yeast. Dev Cell. 2015;35(5):584–599. .
   PubMed Web of Science ®Google Scholar
• Wang CW, Miao YH, Chang YS. A sterol-enriched vacuolar microdomain mediates stationary phase lipophagy in budding yeast. J Cell Biol. 2014;206(3):357–366.
   PubMed Web of Science ®Google Scholar
• Tsuji T, Fujimoto M, Tatematsu T, et al. Niemann-Pick type C proteins promote microautophagy by expanding raft-like membrane domains in the yeast vacuole. Elife. 2017;6:e25960.
   PubMed Web of Science ®Google Scholar
• Oku M, Maeda Y, Kagohashi Y, et al. Evidence for ESCRT- and clathrin-dependent microautophagy. J Cell Biol. 2017;216(10):3263–3274. .
   PubMed Web of Science ®Google Scholar
• Mochida K, Oikawa Y, Kimura Y, et al. Receptor-mediated selective autophagy degrades the endoplasmic reticulum and the nucleus. Nature 2015;522(7556):359–362. .
   PubMed Web of Science ®Google Scholar
• Wang ML, Motamed M, Infante RE, et al. Identification of surface residues on Niemann-Pick C2 essential for hydrophobic handoff of cholesterol to NPC1 in lysosomes. Cell Metab. 2010;12(2):166–173. .
   PubMed Web of Science ®Google Scholar
• Kihara A, Noda T, Ishihara N, et al. Two Distinct Vps34 Phosphatidylinositol 3–Kinase Complexes Function in Autophagy and Carboxypeptidase Y Sorting inSaccharomyces cerevisiae. J Cell Biol. 2001;152(3):519–530. .
   PubMed Web of Science ®Google Scholar
• Bouchez I, Pouteaux M, Canonge M, et al. Regulation of lipid droplet dynamics in Saccharomyces cerevisiae depends on the Rab7-like Ypt7p, HOPS complex and V1-ATPase. Biol Open. 2015;4(7):764–775. .
   PubMed Web of Science ®Google Scholar
• Haas A, Scheglmann D, Lazar T, et al. The GTPase Ypt7p of Saccharomyces cerevisiae is required on both partner vacuoles for the homotypic fusion step of vacuole inheritance. Embo J. 1995;14(21):5258–5270.
   PubMed Web of Science ®Google Scholar
• Wichmann H, Hengst L, Gallwitz D. Endocytosis in yeast: evidence for the involvement of a small GTP-binding protein (Ypt7p). Cell. 1992;71:1131–1142.
   PubMed Web of Science ®Google Scholar
• Kim J, Dalton VM, Eggerton KP, et al. Apg7p/Cvt2p is required for the cytoplasm-to-vacuole targeting, macroautophagy, and peroxisome degradation pathways. Mol Biol Cell. 1999;10(5):1337–1351. .
   PubMed Web of Science ®Google Scholar
• Kaushik S, Cuervo AM. AMPK-dependent phosphorylation of lipid droplet protein PLIN2 triggers its degradation by CMA. Autophagy. 2016;12(2):432–438.
   PubMed Web of Science ®Google Scholar
• Ma SY, Sun KS, Zhang M, et al. Disruption of Plin5 degradation by CMA causes lipid homeostasis imbalance in NAFLD. Liver Int. 2020;40(10):2427–2438. .
   PubMed Web of Science ®Google Scholar
• Madrigal-Matute J, Cuervo AM. Regulation of liver metabolism by autophagy. Gastroenterology. 2016;150(2):328–339.
   PubMed Web of Science ®Google Scholar
• Ueno T, Komatsu M. Autophagy in the liver: functions in health and disease. Nat Rev Gastroenterol Hepatol. 2017;14:170–184.
   PubMed Web of Science ®Google Scholar
• Musso G, Cassader M, Gambino R. Non-alcoholic steatohepatitis: emerging molecular targets and therapeutic strategies. Nat Rev Drug Discov. 2016;15:249–274.
   PubMed Web of Science ®Google Scholar
• Kounakis K, Chaniotakis M, Markaki M, et al. Emerging roles of lipophagy in health and disease. Front Cell Dev Biol. 2019;7:1–8.
   PubMed Web of Science ®Google Scholar
• Carotti S, Aquilano K, Zalfa F, et al. Lipophagy impairment Is associated with disease progression in NAFLD. Front Physiol. 2020;11:850.
   PubMed Web of Science ®Google Scholar
• Zhu S, Wu Y, Ye X, et al. FGF21 ameliorates nonalcoholic fatty liver disease by inducing autophagy. Mol Cell Biochem. 2016;420(1–2):107–119. .
   PubMed Web of Science ®Google Scholar
• Kim SH, Kim G, Han DH, et al. Ezetimibe ameliorates steatohepatitis via AMP activated protein kinase-TFEB-mediated activation of autophagy and NLRP3 inflammasome inhibition. Autophagy. 2017;13(10):1767–1781. .
   PubMed Web of Science ®Google Scholar
• Pan X, Zhang Y, Kim HG, et al. FOXO transcription factors protect against the diet-induced fatty liver disease. Sci Rep. 2017;7(1):1–12. .
   PubMedGoogle Scholar
• Zhang H, Yan S, Khambu B, et al. Dynamic MTORC1-TFEB feedback signaling regulates hepatic autophagy, steatosis and liver injury in long-term nutrient oversupply. Autophagy. 2018;14(10):1779–1795. .
   PubMed Web of Science ®Google Scholar
• Lim H, Lim YM, Kim KH, et al. A novel autophagy enhancer as a therapeutic agent against metabolic syndrome and diabetes. Nat Comm. 2018;9(1):1438. .
   PubMed Web of Science ®Google Scholar
• Schuster S, Cabrera D, Arrese M, et al. Triggering and resolution of inflammation in NASH. Nat Rev Gastroenterol Hepatol. 2018;15:349–364.
   PubMed Web of Science ®Google Scholar
• Fotbolcu H, Zorlu E. Nonalcoholic fatty liver disease as a multi-systemic disease. World J Gastroenterol. 2016;22(16):4079–4090.
   PubMed Web of Science ®Google Scholar
• Noureddin M, Sanyal AJ. Pathogenesis of NASH: the impact of multiple pathways. Curr Hepatol Rep. 2018;17(4):350–360.
   PubMedGoogle Scholar
• Cotter TG, Rinella M. Nonalcoholic fatty liver disease 2020: the state of the disease. Gastroenterology. 2020;158(7):1851–1864.
   PubMed Web of Science ®Google Scholar
• Goedeke L, Bates J, Vatner DF, et al. Acetyl-CoA carboxylase inhibition reverses NAFLD and hepatic insulin resistance but promotes hypertriglyceridemia in rodents. Hepatology. 2018;68(6):2197–2211. .
   PubMed Web of Science ®Google Scholar
• Calzadilla Bertot L, Adams LA. The natural course of non-alcoholic fatty liver disease. Int J Mol Sci. 2016;17(5):774.
   PubMed Web of Science ®Google Scholar
• Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology. 1998;114(842–5). https://doi.org/10.1016/S0016-5085(98)70599-2
   Google Scholar
• Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism. 2016;65(8):1038–1048.
   PubMed Web of Science ®Google Scholar
• Hansen HH, Feigh M, Veidal SS, et al. Mouse models of nonalcoholic steatohepatitis in preclinical drug development. Drug Discov Today. 2017;22(11):1707–1718. .
   PubMed Web of Science ®Google Scholar
• Van Herck MA, Vonghia L, Francque SM. Animal models of nonalcoholic fatty liver disease-A starter’s guide. Nutrients. 2017;9(10):1072.
   Web of Science ®Google Scholar
• Farrell G, Schattenberg JM, Leclercq I, et al. Mouse models of nonalcoholic steatohepatitis: toward optimization of their relevance to human nonalcoholic steatohepatitis. Hepatology. 2019;69(5):2241–2257. .
   PubMed Web of Science ®Google Scholar
• Santhekadur PK, Kumar DP, Sanyal AJ. Preclinical models of non-alcoholic fatty liver disease. J Hepatol. 2018;68(2):230–237.
   PubMed Web of Science ®Google Scholar
• Guo J, Fang W, Chen X, et al. Upstream stimulating factor 1 suppresses autophagy and hepatic lipid droplet catabolism by activating mTOR. FEBS Lett. 2018;592(16):2725–2738. .
   PubMed Web of Science ®Google Scholar
• Machado MV, Michelotti GA, Xie G, et al. Mouse models of diet-induced nonalcoholic steatohepatitis reproduce the heterogeneity of the human disease. PLoS One. 2015;10(5):e0127991. .
   PubMed Web of Science ®Google Scholar
• Song YM, Lee YH, Kim JW, et al. Metformin alleviates hepatosteatosis by restoring SIRT1-mediated autophagy induction via an AMP-activated protein kinase-independent pathway. Autophagy. 2015;11(1):46–59. .
   PubMed Web of Science ®Google Scholar
• Gluchowski NL, Gabriel KR, Chitraju C, et al. Hepatocyte deletion of triglyceride-synthesis enzyme Acyl CoA: diacylglycerol acyltransferase 2 reduces steatosis without increasing inflammation or fibrosis in mice. Hepatology. 2019;70(6):1972–1985. .
   PubMed Web of Science ®Google Scholar
• Donnelly KL, Smith CI, Schwarzenberg SJ, et al. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115(5):1343–1351. .
   PubMed Web of Science ®Google Scholar
• Kohjima M, Enjoji M, Higuchi N, et al. Re-evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease. Int J Mol Med. 2007;20(3):351–358.
   PubMed Web of Science ®Google Scholar
• Steneberg P, Sykaras AG, Backlund F, et al. Hyperinsulinemia enhances hepatic expression of the fatty acid transporter Cd36 and provokes hepatosteatosis and hepatic insulin resistance. J Biol Chem. 2015;290(31):19034–19043. .
   PubMed Web of Science ®Google Scholar
• Ipsen DH, Lykkesfeldt J, Tveden-Nyborg P. Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease. Cell Mol Life Sci. 2018;75(18):3313–3327.
   PubMed Web of Science ®Google Scholar
• Pettinelli P, Videla LA. Up-regulation of PPAR-gamma mRNA expression in the liver of obese patients: an additional reinforcing lipogenic mechanism to SREBP-1c induction. J Clin Endocrinol Metab. 2011;96(5):1424–1430.
   PubMed Web of Science ®Google Scholar
• Nagaya T, Tanaka N, Suzuki T, et al. Down-regulation of SREBP-1c is associated with the development of burned-out NASH. J Hepatol. 2010;53(4):724–731. .
   PubMed Web of Science ®Google Scholar
• Yoshioka Y, Hashimoto E, Yatsuji S, et al. Nonalcoholic steatohepatitis: cirrhosis, hepatocellular carcinoma, and burnt-out NASH. J Gastroenterol. 2004;39(12):1215–1218. .
   PubMed Web of Science ®Google Scholar
• Iizuka K, Bruick RK, Liang G, et al. Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis. Proc Natl Acad Sci U S A. 2004;101(19):7281–7286. .
   PubMed Web of Science ®Google Scholar
• Zhang D, Tong X, VanDommelen K, et al. Lipogenic transcription factor ChREBP mediates fructose-induced metabolic adaptations to prevent hepatotoxicity. J Clin Invest. 2017;127(7):2855–2867. .
   PubMed Web of Science ®Google Scholar
• Benhamed F, Denechaud PD, Lemoine M, et al. The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin resistance in mice and humans. J Clin Invest. 2012;122(6):2176–2194. .
   PubMed Web of Science ®Google Scholar
• Alkhouri N, Lawitz E, Noureddin M, et al. GS-0976 (Firsocostat): an investigational liver-directed acetyl-CoA carboxylase (ACC) inhibitor for the treatment of non-alcoholic steatohepatitis (NASH). Expert Opin Investig Drugs. 2020;29(2):135–141. .
   PubMed Web of Science ®Google Scholar
• Gapp B, Jourdain M, Bringer P, et al. Farnesoid X Receptor Agonism, Acetyl-Coenzyme A Carboxylase Inhibition, and Back Translation of Clinically Observed Endpoints of De NovoLipogenesis in a Murine NASH Model. Hepatol Commun. 2020;4(1):109–125. .
   PubMed Web of Science ®Google Scholar
• Kim CW, Addy C, Kusunoki J, et al. Acetyl CoA carboxylase inhibition reduces hepatic steatosis but elevates plasma triglycerides in mice and humans: a bedside to bench investigation. Cell Metab. 2017;26(3):576. .
   PubMed Web of Science ®Google Scholar
• Bates J, Vijayakumar A, Ghoshal S, et al. Acetyl-CoA carboxylase inhibition disrupts metabolic reprogramming during hepatic stellate cell activation. J Hepatol. 2020;73(4):896–905. .
   PubMedGoogle Scholar
• Petersen MC, Shulman GI. Mechanisms of insulin action and insulin resistance. Physiol Rev. 2018;98:2133–2223.
   PubMed Web of Science ®Google Scholar
• Tilg H, Moschen AR, Roden M. NAFLD and diabetes mellitus. Nat Rev Gastroenterol Hepatol. 2017;14(1):32–42.
   PubMed Web of Science ®Google Scholar
• Salameh H, Hanayneh MA, Masadeh M, et al. PNPLA3 as a genetic determinant of risk for and severity of non-alcoholic fatty liver disease spectrum. J Clin Transl Hepatol. 2016;4(3):175–191. .
   PubMed Web of Science ®Google Scholar
• Wang Y, Kory N, BasuRay S, et al. PNPLA3, CGI-58, and inhibition of hepatic triglyceride hydrolysis in mice. Hepatology. 2019;69(6):2427–2441. .
   PubMed Web of Science ®Google Scholar
• Li JZ, Huang Y, Karaman R, et al. Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis. J Clin Invest. 2012;122(11):4130–4144. .
   PubMed Web of Science ®Google Scholar
• Haemmerle G, Lass A, Zimmermann R, et al. Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science. 2006;312(5774):734–737. .
   PubMed Web of Science ®Google Scholar
• Wu JW, Wang SP, Alvarez F, et al. Deficiency of liver adipose triglyceride lipase in mice causes progressive hepatic steatosis. Hepatology. 2011;54(1):122–132. .
   PubMed Web of Science ®Google Scholar
• Ong KT, Mashek MT, Bu SY, et al. Adipose triglyceride lipase is a major hepatic lipase that regulates triacylglycerol turnover and fatty acid signaling and partitioning. Hepatology. 2011;53(1):116–126. .
   PubMed Web of Science ®Google Scholar
• Yang L, Li P, Fu S, et al. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab. 2010;11(6):467–478. .
   PubMed Web of Science ®Google Scholar
• Okada H, Takabatake R, Honda M, et al. Peretinoin, an acyclic retinoid, suppresses steatohepatitis and tumorigenesis by activating autophagy in mice fed an atherogenic high-fat diet. Oncotarget. 2017;8(25):39978–39993. .
   PubMedGoogle Scholar
• Kim KH, Jeong YT, Oh H, et al. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat Med. 2013;19(1):83–92. .
   PubMed Web of Science ®Google Scholar
• Ma D, Molusky MM, Song J, et al. Autophagy deficiency by hepatic FIP200 deletion uncouples steatosis from liver injury in NAFLD. Mol Endocrinol. 2013;27(10):1643–1654. .
   PubMedGoogle Scholar
• Kwanten WJ, Vandewynckel YP, Martinet W, et al. Hepatocellular autophagy modulates the unfolded protein response and fasting-induced steatosis in mice. Am J Physiol Gastrointest Liver Physiol. 2016;311(4):G599–G609. .
   PubMed Web of Science ®Google Scholar
• Li Y, Chao X, Yang L, et al. Impaired fasting-induced adaptive lipid droplet biogenesis in liver-specific Atg5-deficient mouse liver is mediated by persistent nuclear factor-like 2 activation. Am J Pathol. 2018;188(8):1833–1846. .
   PubMed Web of Science ®Google Scholar
• Takahashi SS, Sou YS, Saito T, et al. Loss of autophagy impairs physiological steatosis by accumulation of NCoR1. Life Sci Alliance. 2020;3(1):e201900513. .
   PubMed Web of Science ®Google Scholar
• Fukushima H, Yamashina S, Arakawa A, et al. Formation of p62-positive inclusion body is associated with macrophage polarization in non-alcoholic fatty liver disease. Hepatol Res. 2018;48(9):757–767. .
   PubMed Web of Science ®Google Scholar
• Koga H, Kaushik S, Cuervo AM. Altered lipid content inhibits autophagic vesicular fusion. Faseb J. 2010;24(8):3052–3065.
   PubMed Web of Science ®Google Scholar
• Hattori K, Naguro I, Runchel C, et al. The roles of ASK family proteins in stress responses and diseases. Cell Commun Signal. 2009;7(1):9. .
   PubMedGoogle Scholar
• Challa TD, Wueest S, Lucchini FC, et al. Liver ASK1 protects from non-alcoholic fatty liver disease and fibrosis. EMBO Mol Med. 2019;11(10):e10124. .
   PubMed Web of Science ®Google Scholar
• Wang PX, Ji YX, Zhang XJ, et al. Corrigendum: targeting CASP8 and FADD-like apoptosis regulator ameliorates nonalcoholic steatohepatitis in mice and nonhuman primates. Nat Med. 2017;23(10):1241. .
   PubMed Web of Science ®Google Scholar
• Ye P, Xiang M, Liao H, et al. Dual-specificity phosphatase 9 protects against nonalcoholic fatty liver disease in mice through ASK1 suppression. Hepatology. 2019;69(1):76–93. .
   PubMed Web of Science ®Google Scholar
• Wang Y, Wen H, Fu J, et al. Hepatocyte TNF receptor-associated factor 6 aggravates hepatic inflammation and fibrosis by promoting lysine 6-linked polyubiquitination of apoptosis signal-regulating kinase 1. Hepatology. 2020;71(1):93–111. .
   PubMed Web of Science ®Google Scholar
• Shiratori Y, Ichida T, Geerts A, et al. Modulation of collagen synthesis by fat-storing cells, isolated from CCl4- or vitamin A-treated rats. Dig Dis Sci. 1987;32(11):1281–1289. .
   PubMed Web of Science ®Google Scholar
• Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol. 2017;14(7):397–411.
   PubMed Web of Science ®Google Scholar
• Wake K. “Sternzellen” in the liver: perisinusoidal cells with special reference to storage of vitamin A. Am J Anat. 1971;132(4):429–462.
   PubMedGoogle Scholar
• Hellerbrand C, Stefanovic B, Giordano F, et al. The role of TGFbeta1 in initiating hepatic stellate cell activation in vivo. J Hepatol. 1999;30(1):77–87. .
   PubMed Web of Science ®Google Scholar
• Thoen LF, Guimaraes EL, Dolle L, et al. A role for autophagy during hepatic stellate cell activation. J Hepatol. 2011;55(6):1353–1360. .
   PubMed Web of Science ®Google Scholar
• Hernández-Gea V, Ghiassi-Nejad Z, Rozenfeld R, et al. Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues. Gastroenterology. 2012;142(4):938–946. .
   PubMed Web of Science ®Google Scholar
• Meng D, Li Z, Wang G, et al. Carvedilol attenuates liver fibrosis by suppressing autophagy and promoting apoptosis in hepatic stellate cells. Biomed Pharmacother. 2018;108:1617–1627.
   PubMed Web of Science ®Google Scholar
• Bai F, Huang Q, Nie J, et al. Trolline ameliorates liver fibrosis by inhibiting the NF-κB pathway, promoting HSC apoptosis and suppressing autophagy. Cell Physiol Biochem. 2017;44(2):436–446. .
   PubMedGoogle Scholar
• Liu N, Feng J, Lu X, et al. Isorhamnetin inhibits liver fibrosis by reducing autophagy and inhibiting extracellular matrix formation via the TGF-. Mediators Inflamm. 2019;2019:6175091.
   PubMed Web of Science ®Google Scholar
• Zhang XL, Chen ZN, Huang QF, et al. Methyl helicterate inhibits hepatic stellate cell activation through modulation of apoptosis and autophagy. Cell Physiol Biochem. 2018;51(2):897–908. .
   PubMedGoogle Scholar
• Qiu S, Xu H, Lin Z, et al. The blockade of lipophagy pathway is necessary for docosahexaenoic acid to regulate lipid droplet turnover in hepatic stellate cells. Biomed Pharmacother. 2019;109:1841–1850.
   PubMed Web of Science ®Google Scholar
• Paik YH, Schwabe RF, Bataller R, et al. Toll-like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells. Hepatology. 2003;37(5):1043–1055. .
   PubMed Web of Science ®Google Scholar
• Takahashi M, Ogasawara K, Takeda K, et al. LPS induces NK1.1+ alpha beta T cells with potent cytotoxicity in the liver of mice via production of IL-12 from Kupffer cells. J Immunol. 1996;156(7):2436–2442.
   PubMed Web of Science ®Google Scholar
• Chen M, Liu J, Yang W, et al. Lipopolysaccharide mediates hepatic stellate cell activation by regulating autophagy and retinoic acid signaling. Autophagy. 2017;13(11):1813–1827. .
   PubMed Web of Science ®Google Scholar
• Koliaki C, Szendroedi J, Kaul K, et al. Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis. Cell Metab. 2015;21(5):739–746. .
   PubMed Web of Science ®Google Scholar
• Pallichankandy S, Rahman A, Thayyullathil F, et al. ROS-dependent activation of autophagy is a critical mechanism for the induction of anti-glioma effect of sanguinarine. Free Radic Biol Med. 2015;89:708–720.
   PubMed Web of Science ®Google Scholar
• Zhang Z, Zhao S, Yao Z, et al. Autophagy regulates turnover of lipid droplets via ROS-dependent Rab25 activation in hepatic stellate cell. Redox Biol. 2017;11:322–334.
   PubMed Web of Science ®Google Scholar
• Lodder J, Denaes T, Chobert MN, et al. Macrophage autophagy protects against liver fibrosis in mice. Autophagy. 2015;11(8):1280–1292. .
   PubMed Web of Science ®Google Scholar
• Liu K, Zhao E, Ilyas G, et al. Impaired macrophage autophagy increases the immune response in obese mice by promoting proinflammatory macrophage polarization. Autophagy. 2015;11(2):271–284. .
   PubMed Web of Science ®Google Scholar
• Remmerie A, Scott CL. Macrophages and lipid metabolism. Cell Immunol. 2018;330:27–42.
   PubMed Web of Science ®Google Scholar
• Ioannou GN, Haigh WG, Thorning D, et al. Hepatic cholesterol crystals and crown-like structures distinguish NASH from simple steatosis. J Lipid Res. 2013;1061:19–44.
   Google Scholar
• Leroux A, Ferrere G, Godie V, et al. Toxic lipids stored by Kupffer cells correlates with their pro-inflammatory phenotype at an early stage of steatohepatitis. J Hepatol. 2012;57(1):141–149. .
   PubMed Web of Science ®Google Scholar
• Jindal A, Bruzzì S, Sutti S, et al. Fat-laden macrophages modulate lobular inflammation in nonalcoholic steatohepatitis (NASH). Exp Mol Pathol. 2015;99(1):155–162. .
   PubMed Web of Science ®Google Scholar
• Huang W, Metlakunta A, Dedousis N, et al. Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance. Diabetes. 2010;59(2):347–357. .
   PubMed Web of Science ®Google Scholar
• Diehl KL, Vorac J, Hofmann K, et al. Kupffer cells sense free fatty acids and regulate hepatic lipid metabolism in high-fat diet and inflammation. Cells. 2020;9(10):2258. .
   Web of Science ®Google Scholar
• Miyao M, Kotani H, Ishida T, et al. Pivotal role of liver sinusoidal endothelial cells in NAFLD/NASH progression. Lab Invest. 2015;95(10):1130–1144. .
   PubMed Web of Science ®Google Scholar
• Hammoutene A, Biquard L, Lasselin J, et al. A defect in endothelial autophagy occurs in patients with non-alcoholic steatohepatitis and promotes inflammation and fibrosis. J Hepatol. 2020;72(3):528–538. .
   PubMed Web of Science ®Google Scholar
• Ruart M, Chavarria L, Campreciós G, et al. Impaired endothelial autophagy promotes liver fibrosis by aggravating the oxidative stress response during acute liver injury. J Hepatol. 2019;70(3):458–469. .
   PubMed Web of Science ®Google Scholar
• Duval C, Thissen U, Keshtkar S, et al. Adipose tissue dysfunction signals progression of hepatic steatosis towards nonalcoholic steatohepatitis in C57Bl/6 mice. Diabetes. 2010;59(12):3181–3191. .
   PubMed Web of Science ®Google Scholar
• Kovsan J, Bluher M, Tarnovscki T, et al. Altered autophagy in human adipose tissues in obesity. J Clin Endocrinol Metab. 2011;96(2):E268–77. .
   PubMed Web of Science ®Google Scholar
• Kosacka J, Kern M, Kloting N, et al. Autophagy in adipose tissue of patients with obesity and type 2 diabetes. Mol Cell Endocrinol. 2015;409:21–32.
   PubMed Web of Science ®Google Scholar
• Zhang X, Wu D, Wang C, et al. Sustained activation of autophagy suppresses adipocyte maturation via a lipolysis-dependent mechanism. Autophagy. 2019;16(9):1668–1682. .
   PubMed Web of Science ®Google Scholar
• Tacke F. Targeting hepatic macrophages to treat liver diseases. J Hepatol. 2017;66(6):1300–1312.
   PubMed Web of Science ®Google Scholar
• Mendez-Sanchez N, Cruz-Ramon VC, Ramirez-Perez OL, et al. New aspects of lipotoxicity in nonalcoholic steatohepatitis. Int J Mol Sci. 2018;19(7):2034. .
   Web of Science ®Google Scholar
• Nielsen J, Christensen AE, Nellemann B, et al. Lipid droplet size and location in human skeletal muscle fibers are associated with insulin sensitivity. Am J Physiol Endocrinol Metab. 2017;313(6):E721–E730. .
   PubMed Web of Science ®Google Scholar
• Onal G, Kutlu O, Gozuacik D, et al. Lipid droplets in health and disease. Lipids Health Dis. 2017;16(1):128. .
   PubMedGoogle Scholar
• Allaire M, Rautou PE, Codogno P, et al. Autophagy in liver diseases: time for translation? J Hepatol. 2019;70(5):985–998. .
   PubMed Web of Science ®Google Scholar
• Kim KE, Jung Y, Min S, et al. Caloric restriction of db/db mice reverts hepatic steatosis and body weight with divergent hepatic metabolism. Sci Rep. 2016;6(1):30111. .
   PubMedGoogle Scholar
• Pi H, Liu M, Xi Y, et al. Long-term exercise prevents hepatic steatosis: a novel role of FABP1 in regulation of autophagy-lysosomal machinery. Faseb J. 2019;33(11):11870–11883. .
   PubMed Web of Science ®Google Scholar
• Chen R, Wang Q, Song S, et al. Protective role of autophagy in methionine-choline deficient diet-induced advanced nonalcoholic steatohepatitis in mice. Eur J Pharmacol. 2016;770:126–133.
   PubMed Web of Science ®Google Scholar
• Kim JH, Sim HA, Jung DY, et al. Poria cocus wolf extract ameliorates hepatic steatosis through regulation of lipid metabolism, inhibition of ER stress, and activation of autophagy via AMPK activation. Int J Mol Sci. 2019;20(19):4801. .
   Web of Science ®Google Scholar
• Li YL, Li XQ, Wang YD, et al. Metformin alleviates inflammatory response in non-alcoholic steatohepatitis by restraining signal transducer and activator of transcription 3-mediated autophagy inhibition in vitro and in vivo. Biochem Biophys Res Commun. 2019;513(1):64–72. .
   PubMed Web of Science ®Google Scholar
• Zhong J, Gong W, Lu L, et al. Irbesartan ameliorates hyperlipidemia and liver steatosis in type 2 diabetic db/db mice via stimulating PPAR-gamma, AMPK/Akt/mTOR signaling and autophagy. Int Immunopharmacol. 2017;42:176–184.
   PubMed Web of Science ®Google Scholar
• Hsiao PJ, Chiou HC, Jiang HJ, et al. Pioglitazone enhances cytosolic lipolysis, beta-oxidation and autophagy to ameliorate hepatic steatosis. Sci Rep. 2017;7(1):9030. .
   PubMedGoogle Scholar
• Shao N, Yu XY, Ma XF, et al. Exenatide delays the progression of nonalcoholic fatty liver disease in C57BL/6 mice, which may involve inhibition of the NLRP3 inflammasome through the mitophagy pathway. Gastroenterol Res Pract. 2018;2018:1864307.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Sowers JR, Ren J. Targeting autophagy in obesity: from pathophysiology to management. Nat Rev Endocrinol. 2018;14:356–376.
   PubMed Web of Science ®Google Scholar
• Wan J, Weiss E, Ben Mkaddem S, et al. LC3-associated phagocytosis protects against inflammation and liver fibrosis via immunoreceptor inhibitory signaling. Sci Transl Med. 2020;12(539):eaaw8523. .
   PubMed Web of Science ®Google Scholar