Characterizing the Mechanism Behind the Progression of NAFLD to Hepatocellular Carcinoma

Figures & data

Table 1. Animals models in NAFLD and hepatocellular carcinoma development.

	Obesity	Insulin resistance	Inflammation	NASH	Fibrosis	HCC
Diet models
MCD Deficient in choline and methionine 10% fat, 40% sucrose,	- (weight loss)	-	+	++ (3 weeks)	++ (5–8 weeks)	-
CDAA Deficient in choline, defined L-amino acid	+	+	+	+	+	-
HFD >60% fat, no increase in sugar or cholesterol	++	++	+	± (strain dependent)	-	-
WD >40% fat, 0.2–1% cholesterol, high sucrose	++	-	+	± (strain dependent)	± (strain dependent)	-
High cholesterol-high fructose >40% fat, 0.2% cholesterol, high fructose	++	++	++	++	++	++
CDAA-HFD Deficient in choline, defined L-amino acid >60% fat, 0.2% cholesterol	++	++	++	++ (8–12 weeks)	+ (16–24 weeks)	+ (24–36 weeks)
Toxins/diet-based models
STAM model STZ + HFD	-	++	++	++	+	++ (16–20 weeks)
HFD + DEN	++	++	++	-	-	++ (20 weeks)
CDAA-HFD + DEN	++	++	++	-	-	++ (20 weeks)
WD + CCl4	+	+	++	+	+	++ (24 weeks)
Genetic/toxic/diet-based models
PTEN^-/-toggle="yes">(PMID 15199412) Deletion of PTEN, a tumor-suppressor gene No specific diet	-	++	++	++	++	+ (44 weeks)
AOX^-/- Deletion of acyl-coenzme A Inhibition of β-oxydation No specific diet	-	-	++	+	+	+ (60 weeks)
MAT1A^-/- Deletion of methionine adenosyltransferase No specific diet	-	-	++	+ (32 weeks)	-	+ (72 weeks)
toggle="yes">foz/foz Alms1 mutation, cilial disorder affecting appetite regulation Fed with 40% fat, 0.2% cholesterol, 34% sucrose	++	++	++	++ (16 weeks)	++ (moderate fibrosis at 24–36 weeks)	++ (52 weeks)
toggle="yes">foz/foz Alms1 mutation, cilial disorder affecting appetite regulation Injected with DEN	++	++	++	+	+	++ (24 weeks)
PPARα^-/- PPAR-γ causes insulin sensitization and enhances glucose metabolism Injected with DEN	++	-	++	++	++	+ (24 weeks)
Liver-specific Hnf4α-deficient mice Hnf4α regulates genes involved in lipid and bile acid synthesis, gluconeogenesis, amino acid metabolism and blood coagulation Fed with HFD	++	-	+	+	+	+ (36 weeks
toggle="yes">Mc4r^-/- mice Mutation of appetite regulation gene Fed with 40% fat, 0.2% cholesterol, 34% sucrose	++	++	+	++ (20 weeks)	++ (20 weeks)	+ (48 weeks)
MUP-uPA Tg Express high amounts of uPA Fed with HFD	++	++	++	++ (16 weeks)	++	++ (40 weeks)
DIAMOND Inbred isogenic strain: 60% C57Bl6/J, 40% S129S1/svlm Fed with 42% fat, 0.1% cholesterol, ad libitum glucose/fructose in drinking water	++	++	++	++ (16 weeks)	++ (advanced fibrosis at 36 weeks)	++ (52 weeks)

ALMS1: Alstrom syndrome 1 gene; AOX: Acyl-coenzyme A oxidase; CCl₄: Carbon tetrachloride; CDAA: Choline-deficient L-amino acid-defined; DEN: Diethylnitrosamine; DIAMOND: Diet-induced animal model of NAFLD; HCC: Hepatocellular carcinoma; HFD: High fat diet; MAT1A: Methionine adenosyltransferase 1A; MCD: Methionine choline deficient; MC4R: Melanocortin receptor 4 knockout; NASH: Non-alcoholic steatohepatitis; PTEN: Phosphatase and tensin homolog; STZ: Streptozotocin; uPA: Urokinase plasminogen activator; WD: Western diet.

Figure 1. Morphological patterns of hepatocellular carcinomas in patients with metabolic syndrome/NAFLD.

1. HCC arising in a patient with cirrhosis (A) well-limited encapsulated nodule of 3 cm within a cirrhotic liver; (B) Moderately differentiated HCC (hematein & eosin staining); (C) Nontumoral liver showing cirrhotic nodules (trichrome staining). 2. HCC arising in a patient without advanced chronic liver disease (D) well-limited nodule of 6 cm; (E) Well-differentiated HCC (hematein and eosin staining); (F) Nontumoral liver showing normal architecture with steatosis (trichrome staining). 3. HCC arising in a pre-existing hepatocellular adenoma (G) well-limited nodule of 4 cm showing hemorrhagic areas in a background normal liver, (H) Well-differentiated HCC (hematein & eosin staining); (I) β-catenin immunostaining showing nuclear positivity of tumoral hepatocytes from the hepatocellular adenoma component.

HCC: Hepatocellular carcinoma; NAFLD: Non-alcoholic fatty liver disease.

Figure 2. Hepatocellular carcinoma developed in a patient with NAFLD.

(A) Macroscopic view showing a large heterogeneous tumor nodule with firm brown and soft yellowish areas. Histological analysis showing (B) at low magnification an encapsulated tumor arising in a normal liver, (C & D) different microscopic patterns (architectural and cytological) are observed throughout the tumor.

NAFLD: Non-alcoholic fatty liver disease.

Figure 3. Steatohepatitic variant of hepatocellular carcinoma: main morphological features.

(A) Macroscopic view showing a large, well-limited, unencpasulated yellowish tumor nodule with few hemorragic areas; H&E staining showing (B) steatosis with large droplets with tumoral hepatocytes, (C) presence of ballooned tumoral hepatocytes (arrow) and Mallory-Denk bodies within ballooned cells (black star) and (D) fibrous stoma (black star).

H&E: Hematoxylin and eosin.

Figure 4. Overview of mechanisms implicated in progression of NAFLD toward hepatocellular carcinoma.