675
Views
1
CrossRef citations to date
0
Altmetric
Review Article

The hedgehog pathway in nonalcoholic fatty liver disease

&
Pages 264-278 | Received 10 Jul 2017, Accepted 02 Mar 2018, Published online: 20 Mar 2018

References

  • Al-Bahrani R, Nagamori S, Leng R, Petryk A, Sergi C. 2015. Differential expression of sonic hedgehog protein in human hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Pathol Oncol Res. 21:901–908.
  • Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, Mills PR, Keach JC, Lafferty HD, Stahler A, et al. 2015. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 149:389–397 e10.
  • Arab JP, Karpen SJ, Dawson PA, Arrese M, Trauner M. 2017. Bile acids and nonalcoholic fatty liver disease: Molecular insights and therapeutic perspectives. Hepatology. 65:350–362.
  • Arensdorf AM, Marada S, Ogden SK. 2016. Smoothened regulation: a tale of two signals. Trends Pharmacol Sci. 37:62–72.
  • Atwood SX, Li M, Lee A, Tang JY, Oro AE. 2013. GLI activation by atypical protein kinase C iota/lambda regulates the growth of basal cell carcinomas. Nature. 494:484–488.
  • Barnes EA, Kong M, Ollendorff V, Donoghue DJ. 2001. Patched1 interacts with cyclin B1 to regulate cell cycle progression. Embo J. 20:2214–2223.
  • Belgacem YH, Borodinsky LN. 2011. Sonic hedgehog signaling is decoded by calcium spike activity in the developing spinal cord. Proc Natl Acad Sci USA. 108:4482–4487.
  • Bijlsma MF, Borensztajn KS, Roelink H, Peppelenbosch MP, Spek CA. 2007. Sonic hedgehog induces transcription-independent cytoskeletal rearrangement and migration regulated by arachidonate metabolites. Cellular Signal. 19:2596–2604.
  • Bijlsma MF, Spek CA, Zivkovic D, van de Water S, Rezaee F, Peppelenbosch MP. 2006. Repression of smoothened by patched-dependent (pro-)vitamin D3 secretion. PLoS Biol. 4:e232
  • Borjigin J, Deng J, Wang MM, Li X, Blackshaw S, Snyder SH. 1999. Circadian rhythm of patched1 transcription in the pineal regulated by adrenergic stimulation and cAMP. J Biol Chem. 274:35012–35015.
  • Briscoe J, Therond PP. 2013. The mechanisms of Hedgehog signalling and its roles in development and disease. Nat Rev Molecul Cell Biol. 14:416–429.
  • Burke R, Nellen D, Bellotto M, Hafen E, Senti KA, Dickson BJ, Basler K. 1999. Dispatched, a novel sterol-sensing domain protein dedicated to the release of cholesterol-modified hedgehog from signaling cells. Cell. 99:803–815.
  • Byrne S, Dlamini N, Lumsden D, Pitt M, Zaharieva I, Muntoni F, King A, Robert L, Jungbluth H. 2015. SIL1-related Marinesco-Sjoegren syndrome (MSS) with associated motor neuronopathy and bradykinetic movement disorder. Neuromuscul Disord. 25:585–588.
  • Cai H, Li H, Li J, Li X, Li Y, Shi Y, Wang D. 2016. Sonic hedgehog signaling pathway mediates development of hepatocellular carcinoma. Tumour Biol. 37:16199–16205.
  • Cai Q, Li J, Gao T, Xie J, Evers BM. 2009. Protein kinase Cdelta negatively regulates hedgehog signaling by inhibition of Gli1 activity. J Biol Chem. 284:2150–2158.
  • Carpenter D, Stone DM, Brush J, Ryan A, Armanini M, Frantz G, Rosenthal A, de Sauvage FJ. 1998. Characterization of two patched receptors for the vertebrate hedgehog protein family. Proc Natl Acad Sci USA. 95:13630–13634.
  • Chan IS, Guy CD, Chen Y, Lu J, Swiderska-Syn M, Michelotti GA, Karaca G, Xie G, Kruger L, Syn WK, et al. 2012. Paracrine Hedgehog signaling drives metabolic changes in hepatocellular carcinoma. Cancer Res. 72:6344–6350.
  • Chan IS, Guy CD, Machado MV, Wank A, Kadiyala V, Michelotti G, Choi S, Swiderska-Syn M, Karaca G, Pereira TA, et al. 2014. Alcohol activates the hedgehog pathway and induces related procarcinogenic processes in the alcohol-preferring rat model of hepatocarcinogenesis. Alcohol Clin Exp Res. 38:787–800.
  • Chavez M, Ena S, Van Sande J, de Kerchove d'Exaerde A, Schurmans S, Schiffmann SN. 2015. Modulation of ciliary phosphoinositide content regulates trafficking and sonic hedgehog signaling output. Dev Cell. 34:338–350.
  • Che L, Yuan YH, Jia J, Ren J. 2012. Activation of sonic hedgehog signaling pathway is an independent potential prognosis predictor in human hepatocellular carcinoma patients. Chin J Cancer Res. 24:323–331.
  • Chen JS, Li HS, Huang JQ, Zhang LJ, Chen XL, Wang Q, Lei J, Feng JT, Liu Q, Huang XH. 2014. Down-regulation of Gli-1 inhibits hepatocellular carcinoma cell migration and invasion. Mol Cell Biochem. 393:283–291.
  • Chen MH, Li YJ, Kawakami T, Xu SM, Chuang PT. 2004. Palmitoylation is required for the production of a soluble multimeric Hedgehog protein complex and long-range signaling in vertebrates. Genes Dev. 18:641–659.
  • Chen X, Lingala S, Khoobyari S, Nolta J, Zern MA, Wu J. 2011. Epithelial mesenchymal transition and hedgehog signaling activation are associated with chemoresistance and invasion of hepatoma subpopulations. J Hepatol. 55:838–845.
  • Chen X, Tukachinsky H, Huang CH, Jao C, Chu YR, Tang HY, Mueller B, Schulman S, Rapoport TA, Salic A. 2011. Processing and turnover of the Hedgehog protein in the endoplasmic reticulum. J Cell Biol. 192:825–838.
  • Chen Y, Sasai N, Ma G, Yue T, Jia J, Briscoe J, Jiang J. 2011. Sonic hedgehog dependent phosphorylation by CK1α and GRK2 is required for ciliary accumulation and activation of smoothened. PLoS Biol. 9:e1001083.
  • Chen Y, Yue S, Xie L, Pu XH, Jin T, Cheng SY. 2011. Dual Phosphorylation of suppressor of fused (Sufu) by PKA and GSK3beta regulates its stability and localization in the primary cilium. J Biol Chem. 286:13502–13511.
  • Cheng WT, Xu K, Tian DY, Zhang ZG, Liu LJ, Chen Y. 2009. Role of Hedgehog signaling pathway in proliferation and invasiveness of hepatocellular carcinoma cells. Int J Oncol. 34:829–836.
  • Chinchilla P, Xiao L, Kazanietz MG, Riobo NA. 2010. Hedgehog proteins activate pro-angiogenic responses in endothelial cells through non-canonical signaling pathways. Cell Cycle. 9:570–579.
  • Choi SS, Omenetti A, Witek RP, Moylan CA, Syn WK, Jung Y, Yang L, Sudan DL, Sicklick JK, Michelotti GA, et al. 2009. Hedgehog pathway activation and epithelial-to-mesenchymal transitions during myofibroblastic transformation of rat hepatic cells in culture and cirrhosis. Am J Physiol Gastrointest Liver Physiol. 297:G1093–G1106.
  • Chuang PT, McMahon AP. 1999. Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature. 397:617–621.
  • Chung SI, Moon H, Ju HL, Cho KJ, Kim DY, Han KH, Eun JW, Nam SW, Ribback S, Dombrowski F, et al. 2015. Hepatic expression of Sonic Hedgehog induces liver fibrosis and promotes hepatocarcinogenesis in a transgenic mouse model. J Hepatol. 64:618–627.
  • Clark JM, Brancati FL, Diehl AM. 2003. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol. 98:960–967.
  • Cooper MK, Porter JA, Young KE, Beachy PA. 1998. Teratogen-mediated inhibition of target tissue response to Shh signaling. Science. 280:1603–1607.
  • Corbit KC, Aanstad P, Singla V, Norman AR, Stainier DY, Reiter JF. 2005. Vertebrate smoothened functions at the primary cilium. Nature. 437:1018–1021.
  • D'Angelo G, Matusek T, Pizette S, Therond PP. 2015. Endocytosis of Hedgehog through dispatched regulates long-range signaling. Dev Cell. 32:290–303.
  • Das S, Samant RS, Shevde LA. 2013. Nonclassical activation of Hedgehog signaling enhances multidrug resistance and makes cancer cells refractory to Smoothened-targeting Hedgehog inhibition. J Biol Chem. 288:11824–11833.
  • Denef N, Neubuser D, Perez L, Cohen SM. 2000. Hedgehog induces opposite changes in turnover and subcellular localization of patched and smoothened. Cell. 102:521–531.
  • Dennler S, Andre J, Alexaki I, Li A, Magnaldo T, ten Dijke P, Wang XJ, Verrecchia F, Mauviel A. 2007. Induction of sonic hedgehog mediators by transforming growth factor-beta: Smad3-dependent activation of Gli2 and Gli1 expression in vitro and in vivo. Cancer Res. 67:6981–6986.
  • Deutsch G, Jung J, Zheng M, Lora J, Zaret KS. 2001. A bipotential precursor population for pancreas and liver within the embryonic endoderm. Development. 128:871–881.
  • Di Magno L, Basile A, Coni S, Manni S, Sdruscia G, D'Amico D, Antonucci L, Infante P, De Smaele E, Cucchi D, et al. 2016. The energy sensor AMPK regulates hedgehog signaling in human cells through a unique Gli1 metabolic checkpoint. Oncotarget. 7:9538–9549.
  • Dorn KV, Hughes CE, Rohatgi R. 2012. A smoothened-Evc2 complex transduces the hedgehog signal at primary cilia. Dev Cell. 23:823–835.
  • Duesterdieck-Zellmer K, Semevolos S, Kinsley M, Riddick T. 2015. Age-related differential gene and protein expression in postnatal cartilage canal and osteochondral junction chondrocytes. Gene Expr Patterns. 17:1–10.
  • Dugum M, Hanouneh I, McIntyre T, Pai R, Aucejo F, Eghtesad B, Zein N. 2016. Sonic hedgehog signaling in hepatocellular carcinoma: a pilot study. Mol Clin Oncol. 4:369–374.
  • Dulai PS, Singh S, Patel J, Soni M, Prokop LJ, Younossi Z, Sebastiani G, Ekstedt M, Hagstrom H, Nasr P, et al. 2017. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta-analysis. Hepatology. 65:1557–1565.
  • Echelard Y, Epstein DJ, St-Jacques B, Shen L, Mohler J, McMahon JA, McMahon AP. 1993. Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell. 75:1417–1430.
  • Ekstedt M, Hagstrom H, Nasr P, Fredrikson M, Stal P, Kechagias S, Hultcrantz R. 2015. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology. 61:1547–1554.
  • Fleig SV, Choi SS, Yang L, Jung Y, Omenetti A, VanDongen HM, Huang J, Sicklick JK, Diehl AM. 2007. Hepatic accumulation of Hedgehog-reactive progenitors increases with severity of fatty liver damage in mice. Lab Invest. 87:1227–1239.
  • Fleury A, Hoch L, Martinez MC, Faure H, Taddei M, Petricci E, Manetti F, Girard N, Mann A, Jacques C, et al. 2016. Hedgehog associated to microparticles inhibits adipocyte differentiation via a non-canonical pathway. Scientific Rep. 6:23479.
  • Garcia-Gonzalo FR, Phua SC, Roberson EC, Garcia G, III, Abedin M, Schurmans S, Inoue T, Reiter JF. 2015. Phosphoinositides regulate ciliary protein trafficking to modulate hedgehog signaling. Dev Cell. 34:400–409.
  • Goetz JA, Singh S, Suber LM, Kull FJ, Robbins DJ. 2006. A highly conserved amino-terminal region of sonic hedgehog is required for the formation of its freely diffusible multimeric form. J Biol Chem. 281:4087–4093.
  • Goetz SC, Ocbina PJ, Anderson KV. 2009. The primary cilium as a Hedgehog signal transduction machine. Methods Cell Biol. 94:199–222.
  • Grzelak CA, Martelotto LG, Sigglekow ND, Patkunanathan B, Ajami K, Calabro SR, Dwyer BJ, Tirnitz-Parker JE, Watkins DN, Warner FJ, et al. 2014. The intrahepatic signalling niche of hedgehog is defined by primary cilia positive cells during chronic liver injury. J Hepatol. 60:143–151.
  • Grzelak CA, Sigglekow ND, Tirnitz-Parker JE, Hamson EJ, Warren A, Maneck B, Chen J, Patkunanathan B, Boland J, Cheng R, et al. 2017. Widespread GLI expression but limited canonical hedgehog signaling restricted to the ductular reaction in human chronic liver disease. PLoS One. 12:e0171480
  • Guha M. 2012. Hedgehog inhibitor gets landmark skin cancer approval, but questions remain for wider potential. Nat Rev Drug Discov. 11:257–258.
  • Guy CD, Suzuki A, Abdelmalek MF, Burchette JL, Diehl AM. for the NC. 2015. Treatment response in the PIVENS trial is associated with decreased hedgehog pathway activity. Hepatology. 61:98–107.
  • Guy CD, Suzuki A, Zdanowicz M, Abdelmalek MF, Burchette J, Unalp A, Diehl AM, Nash CRN. 2012. Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease. Hepatology. 55:1711–1721.
  • Hanna A, Shevde LA. 2016. Hedgehog signaling: modulation of cancer properies and tumor mircroenvironment. Mol Cancer. 15:24.
  • He M, Subramanian R, Bangs F, Omelchenko T, Liem KF Jr, Kapoor TM, Anderson KV. 2014. The kinesin-4 protein Kif7 regulates mammalian Hedgehog signalling by organizing the cilium tip compartment. Nat Cell Biol. 16:663–672.
  • Hirsova P, Ibrahim SH, Bronk SF, Yagita H, Gores GJ. 2013. Vismodegib suppresses TRAIL-mediated liver injury in a mouse model of nonalcoholic steatohepatitis. PLoS One. 8:e70599.
  • Hu L, Lin X, Lu H, Chen B, Bai Y. 2015. An overview of hedgehog signaling in fibrosis. Mol Pharmacol. 87:174–182.
  • Ikram MS, Neill GW, Regl G, Eichberger T, Frischauf AM, Aberger F, Quinn A, Philpott M. 2004. GLI2 is expressed in normal human epidermis and BCC and induces GLI1 expression by binding to its promoter. J Invest Dermatol. 122:1503–1509.
  • Incardona JP, Gaffield W, Kapur RP, Roelink H. 1998. The teratogenic veratrum alkaloid cyclopamine inhibits sonic hedgehog signal transduction. Development. 125:3553–3562.
  • Izzi L, Levesque M, Morin S, Laniel D, Wilkes BC, Mille F, Krauss RS, McMahon AP, Allen BL, Charron F. 2011. Boc and Gas1 each form distinct Shh receptor complexes with Ptch1 and are required for Shh-mediated cell proliferation. Dev Cell. 20:788–801.
  • Jakobs P, Exner S, Schurmann S, Pickhinke U, Bandari S, Ortmann C, Kupich S, Schulz P, Hansen U, Seidler DG, Grobe K. 2014. Scube2 enhances proteolytic Shh processing from the surface of Shh-producing cells. J Cell Sci. 127:1726–1737.
  • Jakobs P, Schulz P, Ortmann C, Schurmann S, Exner S, Rebollido-Rios R, Dreier R, Seidler DG, Grobe K. 2016. Bridging the gap: heparan sulfate and Scube2 assemble Sonic hedgehog release complexes at the surface of producing cells. Sci Rep. 6:26435.
  • Jeng KS, Jeng CJ, Jeng WJ, Sheen IS, Chang CF, Hsiau HI, Hung ZH, Yu MC, Chang FY. 2015. Sonic hedgehog pathway inhibitor mitigates mouse hepatocellular carcinoma. Am J Surg. 210:554–560.
  • Jeng KS, Sheen IS, Jeng WJ, Yu MC, Tsai HH, Chang FY, Su JC. 2012. Blockade of the sonic hedgehog pathway effectively inhibits the growth of hepatoma in mice: an in vivo study. Oncol Lett. 4:1158–1162.
  • Jimeno A, Weiss GJ, Miller WH Jr, Gettinger S, Eigl BJ, Chang AL, Dunbar J, Devens S, Faia K, Skliris G, et al. 2013. Phase I study of the Hedgehog pathway inhibitor IPI-926 in adult patients with solid tumors. Clin Cancer Res. 19:2766–2774.
  • Johnson RW, Nguyen MP, Padalecki SS, Grubbs BG, Merkel AR, Oyajobi BO, Matrisian LM, Mundy GR, Sterling JA. 2011. TGF-beta promotion of Gli2-induced expression of parathyroid hormone-related protein, an important osteolytic factor in bone metastasis, is independent of canonical Hedgehog signaling. Cancer Res. 71:822–831.
  • Jung Y, McCall SJ, Li YX, Diehl AM. 2007. Bile ductules and stromal cells express hedgehog ligands and/or hedgehog target genes in primary biliary cirrhosis. Hepatology. 45:1091–1096.
  • Jung Y, Witek RP, Syn WK, Choi SS, Omenetti A, Premont R, Guy CD, Diehl AM. 2010. Signals from dying hepatocytes trigger growth of liver progenitors. Gut. 59:655–665.
  • Kakisaka K, Cazanave SC, Werneburg NW, Razumilava N, Mertens JC, Bronk SF, Gores GJ. 2012. A hedgehog survival pathway in 'undead' lipotoxic hepatocytes. J hepatol. 57:844–851.
  • Ke YN, Yang WX. 2014. Primary cilium: an elaborate structure that blocks cell division? Gene. 547:175–185.
  • Kim J, Tang JY, Gong R, Kim J, Lee JJ, Clemons KV, Chong CR, Chang KS, Fereshteh M, Gardner D, et al. 2010. Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth. Cancer Cell. 17:388–399.
  • Ko AH, LoConte N, Tempero MA, Walker EJ, Kate Kelley R, Lewis S, Chang WC, Kantoff E, Vannier MW, Catenacci DV, et al. 2016. A phase I study of FOLFIRINOX Plus IPI-926, a hedgehog pathway inhibitor, for advanced pancreatic adenocarcinoma. Pancreas. 45:370–375.
  • Kovacs JJ, Whalen EJ, Liu R, Xiao K, Kim J, Chen M, Wang J, Chen W, Lefkowitz RJ. 2008. Beta-arrestin-mediated localization of smoothened to the primary cilium. Science. 320:1777–1781.
  • Kwon H, Song K, Han C, Chen W, Wang Y, Dash S, Lim K, Wu T. 2016. Inhibition of hedgehog signaling ameliorates hepatic inflammation in mice with nonalcoholic fatty liver disease (NAFLD). Hepatology. 63:1155–1169.
  • Lauth M, Bergstrom A, Shimokawa T, Toftgard R. 2007. Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists. Proc Natl Acad Sci USA. 104:8455–8460.
  • Lee ST, Welch KD, Panter KE, Gardner DR, Garrossian M, Chang CW. 2014. Cyclopamine: from cyclops lambs to cancer treatment. J Agric Food Chem. 62:7355–7362.
  • Li W, Miao S, Miao M, Li R, Cao X, Zhang K, Huang G, Fu B. 2016. Hedgehog signaling activation in hepatic stellate cells promotes angiogenesis and vascular mimicry in hepatocellular carcinoma. Cancer Invest. 34:424–430.
  • Li YH, Luo J, Mosley YY, Hedrick VE, Paul LN, Chang J, Zhang G, Wang YK, Banko MR, Brunet A, et al. 2015. AMP-activated protein kinase directly phosphorylates and destabilizes hedgehog pathway transcription factor GLI1 in medulloblastoma. Cell Rep. 12:599–609.
  • Liu A, Wang B, Niswander LA. 2005. Mouse intraflagellar transport proteins regulate both the activator and repressor functions of Gli transcription factors. Development. 132:3103–3111.
  • Liu J, Chen S, Wang W, Ning BF, Chen F, Shen W, Ding J, Chen W, Xie WF, Zhang X. 2016. Cancer-associated fibroblasts promote hepatocellular carcinoma metastasis through chemokine-activated hedgehog and TGF-β pathways. Cancer Lett. 379:49–59.
  • Lu JT, Zhao WD, He W, Wei W. 2012. Hedgehog signaling pathway mediates invasion and metastasis of hepatocellular carcinoma via ERK pathway. Acta Pharmacol Sin. 33:691–700.
  • Ludwig J, Viggiano TR, McGill DB, Oh BJ. 1980. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc. 55:434–438.
  • Machado MV, Cortez-Pinto H. 2014. Non-alcoholic fatty liver disease: what the clinician needs to know. World J Gastroenterol. 20:12956–12980.
  • Machado MV, Diehl AM. 2016. Pathogenesis of Nonalcoholic Steatohepatitis. Gastroenterology. 150:1769–1777.
  • Machado MV, Michelotti GA, Pereira TA, Boursier J, Kruger L, Swiderska-Syn M, Karaca G, Xie G, Bohnic B, Lindblom KR, et al. 2015. Reduced lipoapoptosis, hedgehog pathway activation and fibrosis in caspase-2 deficient mice with non-alcoholic steatohepatitis. Gut. 64:1148–1157.
  • Machado MV, Michelotti GA, Pereira TA, Xie G, Premont R, Cortez-Pinto H, Diehl AM. 2015. Accumulation of duct cells with activated YAP parallels fibrosis progression in non-alcoholic fatty liver disease. J Hepatol. 63:962–970.
  • Machado MV, Michelotti GA, Xie G, Almeida Pereira T, Boursier J, Bohnic B, Guy CD, Diehl AM. 2015. Mouse models of diet-induced nonalcoholic steatohepatitis reproduce the heterogeneity of the human disease. PLoS One. 10:e0127991.
  • Matusek T, Wendler F, Poles S, Pizette S, D'Angelo G, Furthauer M, Therond PP. 2014. The ESCRT machinery regulates the secretion and long-range activity of Hedgehog. Nature. 516:99–103.
  • Matz-Soja M, Rennert C, Schonefeld K, Aleithe S, Boettger J, Schmidt-Heck W, Weiss TS, Hovhannisyan A, Zellmer S, Kloting N, et al. 2016. Hedgehog signaling is a potent regulator of liver lipid metabolism and reveals a GLI-code associated with steatosis. Elife. 5:e13305.
  • Mavromatakis YE, Lin W, Metzakopian E, Ferri AL, Yan CH, Sasaki H, Whisett J, Ang SL. 2011. Foxa1 and Foxa2 positively and negatively regulate Shh signalling to specify ventral midbrain progenitor identity. Mech Dev. 128:90–103.
  • Merchant JL, Saqui-Salces M. 2014. Inhibition of Hedgehog signaling in the gastrointestinal tract: targeting the cancer microenvironment. Cancer Treat Rev. 40:12–21.
  • Michelotti GA, Machado MV, Diehl AM. 2013. NAFLD, NASH and liver cancer. Nat Rev Gastroenterol Hepatol. 10:656–665.
  • Michelotti GA, Xie G, Swiderska M, Choi SS, Karaca G, Kruger L, Premont R, Yang L, Syn WK, Metzger D, Diehl AM. 2013. Smoothened is a master regulator of adult liver repair. J Clin Invest. 123:2380–2394.
  • Milenkovic L, Weiss LE, Yoon J, Roth TL, Su YS, Sahl SJ, Scott MP, Moerner WE. 2015. Single-molecule imaging of hedgehog pathway protein smoothened in primary cilia reveals binding events regulated by Patched1. Proc Natl Acad Sci USA. 112:8320–8325.
  • Mokdad AA, Lopez AD, Shahraz S, Lozano R, Mokdad AH, Stanaway J, Murray CJ, Naghavi M. 2014. Liver cirrhosis mortality in 187 countries between 1980 and 2010: a systematic analysis. BMC Med. 12:145.
  • Mukhopadhyay S, Wen X, Ratti N, Loktev A, Rangell L, Scales SJ, Jackson PK. 2013. The ciliary G-protein-coupled receptor Gpr161 negatively regulates the Sonic hedgehog pathway via cAMP signaling. Cell. 152:210–223.
  • Musso G, Gambino R, Cassader M, Pagano G. 2011. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med. 43:617–649.
  • Naranjo TW, Lopera DE, Diaz-Granados LR, Duque JJ, Restrepo A, Cano LE. 2010. Histopathologic and immunologic effects of the itraconazole treatment in a murine model of chronic pulmonary paracoccidioidomycosis. Microbes Infect. 12:1153–1162.
  • Naranjo TW, Lopera DE, Diaz-Granados LR, Duque JJ, Restrepo AM, Cano LE. 2011. Combined itraconazole-pentoxifylline treatment promptly reduces lung fibrosis induced by chronic pulmonary paracoccidioidomycosis in mice. Pulm Pharmacol Ther. 24:81–91.
  • Natarajan SK, Ingham SA, Mohr AM, Wehrkamp CJ, Ray A, Roy S, Cazanave SC, Phillippi MA, Mott JL. 2014. Saturated free fatty acids induce cholangiocyte lipoapoptosis. Hepatology. 60:1942–1956.
  • Natarajan SK, Stringham BA, Mohr AM, Wehrkamp CJ, Lu S, Phillippi MA, Harrison-Findik D, Mott JL. 2017. FoxO3 increases miR-34a to cause palmitate-induced cholangiocyte lipoapoptosis. J Lipid Res. 58:866–875.
  • Nault JC, Couchy G, Balabaud C, Morcrette G, Caruso S, Blanc JF, Bacq Y, Calderaro J, Paradis V, Ramos J, et al. 2017. Molecular classification of hepatocellular adenoma associates with risk factors, bleeding, and malignant transformation. Gastroenterology. 152:880–894 e6.
  • Nolan-Stevaux O, Lau J, Truitt ML, Chu GC, Hebrok M, Fernandez-Zapico ME, Hanahan D. 2009. GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation. Genes Dev. 23:24–36.
  • Nusslein-Volhard C, Wieschaus E. 1980. Mutations affecting segment number and polarity in Drosophila. Nature. 287:795–801.
  • Ochoa B, Syn WK, Delgado I, Karaca GF, Jung Y, Wang J, Zubiaga AM, Fresnedo O, Omenetti A, Zdanowicz M, et al. 2010. Hedgehog signaling is critical for normal liver regeneration after partial hepatectomy in mice. Hepatology. 51:1712–1723.
  • Omenetti A, Bass LM, Anders RA, Clemente MG, Francis H, Guy CD, McCall S, Choi SS, Alpini G, Schwarz KB, et al. 2011. Hedgehog activity, epithelial-mesenchymal transitions, and biliary dysmorphogenesis in biliary atresia. Hepatology. 53:1246–1258.
  • Omenetti A, Popov Y, Jung Y, Choi SS, Witek RP, Yang L, Brown KD, Schuppan D, Diehl AM. 2008. The hedgehog pathway regulates remodelling responses to biliary obstruction in rats. Gut. 57:1275–1282.
  • Omenetti A, Syn WK, Jung Y, Francis H, Porrello A, Witek RP, Choi SS, Yang L, Mayo MJ, Gershwin ME, et al. 2009. Repair-related activation of hedgehog signaling promotes cholangiocyte chemokine production. Hepatology. 50:518–527.
  • Pak E, Segal RA. 2016. Hedgehog signal transduction: key players, oncogenic drivers, and cancer therapy. Dev Cell. 38:333–344.
  • Pal K, Hwang SH, Somatilaka B, Badgandi H, Jackson PK, DeFea K, Mukhopadhyay S. 2016. Smoothened determines beta-arrestin-mediated removal of the G protein-coupled receptor Gpr161 from the primary cilium. J Cell Biol. 212:861–875.
  • Pan Y, Wang B. 2007. A novel protein-processing domain in Gli2 and Gli3 differentially blocks complete protein degradation by the proteasome. J Biol Chem. 282:10846–10852.
  • Panakova D, Sprong H, Marois E, Thiele C, Eaton S. 2005. Lipoprotein particles are required for Hedgehog and Wingless signalling. Nature. 435:58–65.
  • Parchure A, Vyas N, Ferguson C, Parton RG, Mayor S. 2015. Oligomerization and endocytosis of Hedgehog is necessary for its efficient exovesicular secretion. Mol Biol Cell. 26:4700–4717.
  • Peluso MO, Campbell VT, Harari JA, Tibbitts TT, Proctor JL, Whitebread N, Conley JM, White KF, Kutok JL, Read MA, et al. 2014. Impact of the Smoothened inhibitor, IPI-926, on smoothened ciliary localization and Hedgehog pathway activity. PLoS One. 9:e90534.
  • Pepinsky RB, Zeng C, Wen D, Rayhorn P, Baker DP, Williams KP, Bixler SA, Ambrose CM, Garber EA, Miatkowski K, et al. 1998. Identification of a palmitic acid-modified form of human Sonic hedgehog. J Biol Chem. 273:14037–14045.
  • Pereira TA, Xie G, Choi SS, Syn WK, Voieta I, Lu J, Chan IS, Swiderska M, Amaral KB, Antunes CM, et al. 2013. Macrophage-derived Hedgehog ligands promotes fibrogenic and angiogenic responses in human schistosomiasis mansoni. Liver Int. 33:149–161.
  • Philips GM, Chan IS, Swiderska M, Schroder VT, Guy C, Karaca GF, Moylan C, Venkatraman T, Feuerlein S, Syn WK, et al. 2011. Hedgehog signaling antagonist promotes regression of both liver fibrosis and hepatocellular carcinoma in a murine model of primary liver cancer. PLoS One. 6:e23943.
  • Pinter M, Sieghart W, Schmid M, Dauser B, Prager G, Dienes HP, Trauner M, Peck-Radosavljevic M. 2013. Hedgehog inhibition reduces angiogenesis by downregulation of tumoral VEGF-A expression in hepatocellular carcinoma. United Eur Gastroenterol J. 1:265–275.
  • Polizio AH, Chinchilla P, Chen X, Kim S, Manning DR, Riobo NA. 2011. Heterotrimeric Gi proteins link Hedgehog signaling to activation of Rho small GTPases to promote fibroblast migration. J Biol Chem. 286:19589–19596.
  • Porter JA, Young KE, Beachy PA. 1996. Cholesterol modification of hedgehog signaling proteins in animal development. Science. 274:255–259.
  • Pratap A, Panakanti R, Yang N, Eason JD, Mahato RI. 2010. Inhibition of endogenous hedgehog signaling protects against acute liver injury after ischemia reperfusion. Pharm Res. 27:2492–2504.
  • Ramsbottom SA, Pownall ME. 2016. Regulation of hedgehog signalling inside and outside the cell. J Dev Biol. 4:23
  • Rangwala F, Guy CD, Lu J, Suzuki A, Burchette JL, Abdelmalek MF, Chen W, Diehl AM. 2011. Increased production of sonic hedgehog by ballooned hepatocytes. J Pathol. 224:401–410.
  • Razumilava N, Gradilone SA, Smoot RL, Mertens JC, Bronk SF, Sirica AE, Gores GJ. 2014. Non-canonical Hedgehog signaling contributes to chemotaxis in cholangiocarcinoma. J Hepatol. 60:599–605.
  • Richardson MM, Jonsson JR, Powell EE, Brunt EM, Neuschwander-Tetri BA, Bhathal PS, Dixon JB, Weltman MD, Tilg H, Moschen AR, et al. 2007. Progressive fibrosis in nonalcoholic steatohepatitis: association with altered regeneration and a ductular reaction. Gastroenterology. 133:80–90.
  • Rimkus TK, Carpenter RL, Qasem S, Chan M, Lo HW. 2016. Targeting the sonic hedgehog signaling pathway: review of smoothened and GLI inhibitors. Cancers (Basel). 8:E22.
  • Rohatgi R, Milenkovic L, Corcoran RB, Scott MP. 2009. Hedgehog signal transduction by Smoothened: pharmacologic evidence for a 2-step activation process. Proc Natl Acad Sci USA. 106:3196–3201.
  • Rohatgi R, Milenkovic L, Scott MP. 2007. Patched1 regulates hedgehog signaling at the primary cilium. Science. 317:372–376.
  • Roy S. 2012. Cilia and Hedgehog: when and how was their marriage solemnized? Differentiat Res Biol Diversity. 83:S43–S48.
  • Sandhiya S, Melvin G, Kumar SS, Dkhar SA. 2013. The dawn of hedgehog inhibitors: vismodegib. J Pharmacol Pharmacother. 4:4–7.
  • Sasaki K, Gotlib JR, Mesa RA, Newberry KJ, Ravandi F, Cortes JE, Kelly P, Kutok JL, Kantarjian HM, Verstovsek S. 2015. Phase II evaluation of IPI-926, an oral Hedgehog inhibitor, in patients with myelofibrosis. Leuk Lymphoma. 56:2092–2097.
  • Schreck KC, Taylor P, Marchionni L, Gopalakrishnan V, Bar EE, Gaiano N, Eberhart CG. 2010. The Notch target Hes1 directly modulates Gli1 expression and Hedgehog signaling: a potential mechanism of therapeutic resistance. Clin Cancer Res. 16:6060–6070.
  • Sicklick JK, Li YX, Choi SS, Qi Y, Chen W, Bustamante M, Huang J, Zdanowicz M, Camp T, Torbenson MS, et al. 2005. Role for hedgehog signaling in hepatic stellate cell activation and viability. Lab Invest. 85:1368–1380.
  • Sicklick JK, Li YX, Jayaraman A, Kannangai R, Qi Y, Vivekanandan P, Ludlow JW, Owzar K, Chen W, Torbenson MS, Diehl AM. 2006. Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis. Carcinogenesis. 27:748–757.
  • Sicklick JK, Li YX, Melhem A, Schmelzer E, Zdanowicz M, Huang J, Caballero M, Fair JH, Ludlow JW, McClelland RE, et al. 2006. Hedgehog signaling maintains resident hepatic progenitors throughout life. Am J Physiol Gastrointest Liver Physiol. 290:G859–G870.
  • Stanton BZ, Peng LF, Maloof N, Nakai K, Wang X, Duffner JL, Taveras KM, Hyman JM, Lee SW, Koehler AN, et al. 2009. A small molecule that binds Hedgehog and blocks its signaling in human cells. Nat Chem Biol. 5:154–156.
  • Stecca B, Mas C, Clement V, Zbinden M, Correa R, Piguet V, Beermann F, Ruiz IAA. 2007. Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways. Proc Natl Acad Sci USA. 104:5895–5900.
  • Stecca B, Ruiz i Altaba A. 2009. A GLI1-p53 inhibitory loop controls neural stem cell and tumour cell numbers. EMBO J. 28:663–676.
  • Swiderska-Syn M, Suzuki A, Guy CD, Schwimmer JB, Abdelmalek MF, Lavine JE, Diehl AM. 2013. Hedgehog pathway and pediatric nonalcoholic fatty liver disease. Hepatology. 57:1814–1825.
  • Syn WK, Agboola KM, Swiderska M, Michelotti GA, Liaskou E, Pang H, Xie G, Philips G, Chan IS, Karaca GF, et al. 2012. NKT-associated hedgehog and osteopontin drive fibrogenesis in non-alcoholic fatty liver disease. Gut. 61:1323–1329.
  • Syn WK, Choi SS, Liaskou E, Karaca GF, Agboola KM, Oo YH, Mi Z, Pereira TA, Zdanowicz M, Malladi P, et al. 2011. Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis. Hepatology. 53:106–115.
  • Syn WK, Jung Y, Omenetti A, Abdelmalek M, Guy CD, Yang L, Wang J, Witek RP, Fearing CM, Pereira TA, et al. 2009. Hedgehog-mediated epithelial-to-mesenchymal transition and fibrogenic repair in nonalcoholic fatty liver disease. Gastroenterology. 137:1478–1488 e8.
  • Syn WK, Oo YH, Pereira TA, Karaca GF, Jung Y, Omenetti A, Witek RP, Choi SS, Guy CD, Fearing CM, et al. 2010. Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease. Hepatology. 51:1998–2007.
  • Syn WK, Witek RP, Curbishley SM, Jung Y, Choi SS, Enrich B, Omenetti A, Agboola KM, Fearing CM, Tilg H, et al. 2009. Role for hedgehog pathway in regulating growth and function of invariant NKT cells. Eur J Immunol. 39:1879–1892.
  • Taipale J, Chen JK, Cooper MK, Wang B, Mann RK, Milenkovic L, Scott MP, Beachy PA. 2000. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature. 406:1005–1009.
  • Taipale J, Cooper MK, Maiti T, Beachy PA. 2002. Patched acts catalytically to suppress the activity of Smoothened. Nature. 418:892–897.
  • Teperino R, Aberger F, Esterbauer H, Riobo N, Pospisilik JA. 2014. Canonical and non-canonical Hedgehog signalling and the control of metabolism. Semin Cell Dev Biol. 33:81–92.
  • Teperino R, Amann S, Bayer M, McGee SL, Loipetzberger A, Connor T, Jaeger C, Kammerer B, Winter L, Wiche G, et al. 2012. Hedgehog partial agonism drives Warburg-like metabolism in muscle and brown fat. Cell. 151:414–426.
  • Tsai CL, Hsu FM, Tzen KY, Liu WL, Cheng AL, Cheng JC. 2015. Sonic Hedgehog inhibition as a strategy to augment radiosensitivity of hepatocellular carcinoma. J Gastroenterol Hepatol. 30:1317–1324.
  • Tukachinsky H, Kuzmickas RP, Jao CY, Liu J, Salic A. 2012. Dispatched and scube mediate the efficient secretion of the cholesterol-modified hedgehog ligand. Cell Rep. 2:308–320.
  • Wang B, Li Y. 2006. Evidence for the direct involvement of {beta}TrCP in Gli3 protein processing. Proc Natl Acad Sci USA. 103:33–38.
  • Wang C, Pan Y, Wang B. 2010. Suppressor of fused and Spop regulate the stability, processing and function of Gli2 and Gli3 full-length activators but not their repressors. Development. 137:2001–2009.
  • Wang X, Zheng Z, Caviglia JM, Corey KE, Herfel TM, Cai B, Masia R, Chung RT, Lefkowitch JH, Schwabe RF, et al. 2016. Hepatocyte TAZ/WWTR1 promotes inflammation and fibrosis in nonalcoholic steatohepatitis. Cell Metab. 24:848–862.
  • Wang Y, Han C, Lu L, Magliato S, Wu T. 2013. Hedgehog signaling pathway regulates autophagy in human hepatocellular carcinoma cells. Hepatology. 58:995–1010.
  • Wheatley DN, Wang AM, Strugnell GE. 1996. Expression of primary cilia in mammalian cells. Cell Biol Int. 20:73–81.
  • Wong RJ, Aguilar M, Cheung R, Perumpail RB, Harrison SA, Younossi ZM, Ahmed A. 2015. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology. 148:547–555.
  • Wong RJ, Cheung R, Ahmed A. 2014. Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S. Hepatology. 59:2188–2195.
  • Xie G, Choi SS, Syn WK, Michelotti GA, Swiderska M, Karaca G, Chan IS, Chen Y, Diehl AM. 2013. Hedgehog signalling regulates liver sinusoidal endothelial cell capillarisation. Gut. 62:299–309.
  • Yang L, Wang Y, Mao H, Fleig S, Omenetti A, Brown KD, Sicklick JK, Li YX, Diehl AM. 2008. Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells. J Hepatol. 48:98–106.
  • Ye F, Jing YY, Guo SW, Yu GF, Fan QM, Qu FF, Gao L, Yang Y, Wu D, Meng Y, et al. 2014. Proliferative ductular reactions correlate with hepatic progenitor cell and predict recurrence in HCC patients after curative resection. Cell Biosci. 4:50.
  • Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. 2016. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 64:73–84.
  • Yue S, Tang LY, Tang Y, Tang Y, Shen QH, Ding J, Chen Y, Zhang Z, Yu TT, Zhang YE, Cheng SY. 2014. Requirement of Smurf-mediated endocytosis of Patched1 in sonic hedgehog signal reception. Elife. 3:e02555.
  • Zhang DW, Li HY, Lau WY, Cao LQ, Li Y, Jiang XF, Yang XW, Xue P. 2014. Gli2 silencing enhances TRAIL-induced apoptosis and reduces tumor growth in human hepatoma cells in vivo. Cancer Biol Ther. 15:1667–1676.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.