Experimental models of metabolic and alcoholic fatty liver disease

Table 1 Experimental studies modeling the effect of metabolic syndrome risk factors and alcohol consumption on liver injury outcomes in rodent and cell culture models

Ref.	Experimental model details	Biochemistry	Anatomy and histology		mRNA and protein expression
Alwahsh et al[84]	(1) Animal: 10 wk male Sprague- Dawley rat; (2) Initial weight: 270-310 g; (3) Diet: LD control, LD with 30% kcal from fructose, 30% kcal from EtOH, or LD with both fructose and EtOH; and (4) Duration: 28 d	(1) ↑ ALT; (2) ↑ liver and plasma TG; (3) ↑ plasma leptin; (4) ↓ plasma HDL; (5) ↓ plasma albumin; and (6) No dif. in leptin or hepatic TG between LD-EtOH and LD- fructose-EtOH	(1) Portal inflammatory infiltration and stage 1 fibrosis (LD-EtOH); (2) Periportal macrosteatosis (LD- fructose); and (3) Portal inflammation, periportal macrosteatosis, fibrosis (LD- fructose-EtOH)		(1) ↑ leptin; (2) ↑ ACC-2; (3) ↑ lipase in LD-EtOH, but ↓ in LD-fructose and LD-fructose-EtOH; (4) ↓ IRS-1, IRS-2 (fructose groups); and (5) ↑ CD36, CPT-1α, PPARα in LD- EtOH and LD-fructose, but no change in LD-fructose-EtOH
Bucher et al[112]	(1) Animal: 7 wk male C57BL/6J Mouse; (2) Initial weight: 20-23 g; (3) Diet: Control (3 kcal/g food; 16% kcal protein) or HFD (5.5 kcal/g; 60% kcal SFA); 10 g/kg/d EtOH in drinking water; and (4) Duration: 4 mo	(1) ↑ ALT, but ↓ ALT compared to EtOH-naïve HFD; (2) ↑ cholesterol, but ↓ cholesterol compared to EtOH-naïve HFD; (3) ↑ TG↑ serum glucose; (4) ↑ serum insulin; and (5) ↑ MUFA and ↓ SFA (compared to HFD)	(1) Mediovesicular and macrovacular steatosis and (2) No dif. in necroinflammation or perisinusoidal fibrosis between HFD and HFD-EtOH		(1) ↑ genes for apoptosis inhibition, acetyl-CoA synthesis, lipogenesis, mitochondrial functions (NADH dehydrogenase, COX, ATP synthase), and proteolysis; (2) ↓ genes for apoptosis (BCL-2 homologs), fibrosis (collagen), chemotaxis, oxidative stress (GPx, HMOX-1, SOD); and (3) ↓ CYP2E1 protein levels
Carmiel-Haggai et al[94]	(1) Animal: 15 wk male fa/fa Zucker Rat; (2) Initial weight: 595 ± 35 g (obese), 316 ± 32 g (lean controls); and (3) Diet: 35% v/v EtOH in saline every 12 h for 3 d; final dose was 4 g/kg EtOH	(1) ↑ ALT; (2) ↑ NEFA; (3) ↑ LPO by-products (4-HNE, MDA); and (4) ↓ CYP2E1 activity	(1) Macrovesicular steatosis (EtOH- naïve fa/fa) and (2) Lobular microvesicular, central macrosteatosis, inflammation (EtOH-fed fa/fa)		(1) ↓ GSH, GPx, GR; (2) ↓ GSSG (EtOH-fed and EtOH-naïve fa/fa); (3) ↓ catalase, SOD; (4) ↑ iNOS; (5) ↑ caspase 3, caspase 8; (6) ↑ BCL-XL, FAS ligand; and (7) ↑ BCL-2, BAX (EtOH-fed and EtOH-naïve fa/fa)
Duly et al[80]	(1) Animal: 6-8 wk male C57BL/6 Mouse; (2) Initial weight: 20 g; (3) Diet: chow (12% kcal fat) or HFD (45% kcal fat, 0.25% cholesterol); 2 g/kg EtOH in saline twice per wk; and (4) Duration: 12 wk	(1) ↑ TG (chow-EtOH, but not HFD or HFD-EtOH); (2) ↑ cholesterol, HDL, LDL (but no difference between HFD and HFD- EtOH); and (3) ↑ serum insulin	(1) Steatosis and lipid accumulation; (2) Collagen deposition; (3) ↑ cellular infiltration; (4) ↑ CD45+ leukocytes; (5) ↑ F4/80+ Kupffer cells; and (6) ↑ vimentin+ HSCs		(1) ↑ SREBP-1; (2) ↑ SCD-1; (3) ↑ PPARα; (4) ↓ ACOX-1; (5) No dif. in TGFβ or HSP90; and (6) ↑ collagen I, PAI-1 (EtOH-naïve HFD)
Everitt et al[87]	(1) Animal: 12 wk male ob/ob C57BL/6-J/Rj-ob mouse; (2) Diet: PUFA-enriched LD with 27.5% EtOH or isocaloric maltodextrin; and (3) Duration: 4 wk	(1) ↑ ALT/AST; (2) ↑ hepatic TG; (3) ↑ hepatic cholesterol; (4) ↑ hepatic lactate; (5) ↓ hepatic pyruvate; (6) No dif. in BAL between EtOH-fed; and (7) ob/ob and EtOH-fed lean mice	Steatosis in EtOH-fed ob/ob		(1) ↑ mTOR, PPARγ, FGF-21, FSP-27; (2) ↑ SIRT-1, pAMPKα, AMPKα, pACC (ob compared to lean; EtOH did not have an effect); (3) ↑ adipose TNFα, ↓ hepatic TNFα; (4) ↑ cytosolic lipin-1 protein levels; (5) ↓ nuclear lipin-1 protein levels; (6) ↓ PGC-1α; and (7) ↓ ACOX-1
Gäbele et al[77]	(1) Animal: 12 wk female Balb/c mouse; (2) Diet: Chow or HFD [17% fat (50% lard, 50% cacao-butter), 1.25% cholesterol, 0.5% cholate]; 5% EtOH in ad libitum; and (3) Duration: 6 wk	(1) ↑ hepatic TG; (2) ↑ portal blood LPS; and (3) ↓ BAL (not statistically significant)	(1) Steatosis in HFD-fed mice; (2) ↑ 4-HNE; (3) ↑ αSMA+ cells; (4) ↑ collagen I; and (5) ↑ ECM deposition		(1) ↑ p47phox, TNF, TGFβ, collagen I; (2) ↑ TLR-4 in HFD mice, with no effect by EtOH; (3) ↑ αSMA protein levels; and (4) ↓ CYP2E1 protein levels in HFD
Gopal et al[79]	(1) Animal: 6-8 wk male C57BL/6 mouse; (2) Diet: Chow or HFD (45% kcal fat) for 10 wk, then LD control or 5% v/v EtOH LD for 4 wk additionally; and (3) Drug: HFD mice also given 1000 U/kg Cu/Zn SOD-1 with polylysine- PEG copolymer in 10 mM HEPES every 2 d for 2 wk	(1) ↑ ALT; (2) ↑ FFA; (3) ↓ leptin; (4) nanoSOD treatment counteracted the above effects; and (5) No dif. in MDA between groups	(1) ↑ adipose mass by HFD, but ↓ fat/body weight ratio by HFD- EtOH; (2) ↑ microvesicular steatosis (in all mice); (3) ↑ macrovesicular steatosis; (4) ↑ inflammatory nodules; (5) ↑ hepatocyte ballooning; and (6) ↑ MCP-1 protein levels, ↓ MCP-1 in HFD-EtOH mice treated with nanoSOD		(1) ↑ adipose CYP2E1 protein levels, ↓ CYP2E1 by nanoSOD; (2) ↑ hepatic CYP2E1, ADH, catalase, ↓ CYP2E1 and ADH, but ↑ catalase by nanoSOD; (3) ↑ PPARα, ACOX-1 in HFD, further ↑ ACOX-1 by EtOH, further ↑ for both by nanoSOD; and (4) ↑ CCL-2, MMP-12; ↓ by nanoSOD
Jung et al[108]	(1) Animal: Female C57BL/6J mouse; (2) Diet: Control (69% carbohydrates, 12% fat, 19% protein) or FFC (60% carbohydrates, 25% fat, 15% protein, 50% wt/wt fructose, 0.16% wt/wt cholesterol); Diets enriched with 2.5 g/kg EtOH, isocaloric beer (4.9% v/v EtOH), or isocaloric diet; and (3) Duration: 7 wk	(1) ↑ TG; ↓ in beer-treated FFC compared to EtOH-treated or naïve and (2) ↓ glucose tolerance in all FFC-fed groups	(1) ↑ neutrophil granulocytes; ↓ by beer in FFC-fed mice; (2) ↑ NAS; ↓ by beer in FFC-fed mice; (3) ↑ iNOS protein levels; ↓ by beer and EtOH in FFC-fed mice; and (4) ↑ 4-HNE; ↓ by beer and EtOH in FFC-fed mice		(1) ↑ IR, IRS-2 in FFC-EtOH and FFC- beer compared to naïve; no dif. in IRS-1; (2) ↓ adiponectin in FFC and FFC- EtOH, but ↑ in FFC-beer; (3) ↑ hepatic AdipoR1 and SIRT-1 in FFC-beer; and (4) No dif. in PPARγ, AdipoR2, FASN, SREBP-1c, ACOX-1 between groups
Kanuri et al[106]	(1) Animal: 6 wk male ob/ob C57BL/6 mouse; (2) Diet: 2.5 g/kg/d EtOH in drinking water; and (3) Duration: 6 wk	(1) ↑ ALT/AST in ob/ob, but ↓ slightly by EtOH in ob/ob; (2) ↑ TG, cholesterol, HDL, LDL in ob/ob, but no effect by EtOH; and (3) No dif. in FFA	(1) Steatosis, hepatomegaly in ob/ob; (2) Macrovesicular steatosis in EtOH- naïve ob/ob; (3) Microvesicular steatosis in EtOH- fed ob/ob; and (4) ↓ hepatic neutrophils		(1) ↑ PLIN-2, PLIN-3, TNFα, PAI-1 in ob/ob, ↓ PAI-1, PLIN-2, PLIN-3 by EtOH; (2) ↓ IRS-1, IRS-2, adiponectin, SIRT- 1 in ob/ob; ↑ adiponectin, SIRT-1 by EtOH; (3) No effect by EtOH on PPARγ, ACOX-1, SREBP-1c, IRS-1, IRS02, GLUT-4, glucokinase, PEPCK; and (4) No dif. in hepatic ACOX-1, PPARγ
Kitagawa et al[93]	(1) Animal: 8 wk female KK-Ay mouse; (2) Diet: LD with 5% EtOH or isocaloric maltodextrin; Single gavage of 4 g/kg EtOH or gavage on after 11 d; (3) Drug: 0.1 g/L rifaximin (RFX); and (4) Duration: 10 d	(1) ↑ ALT; (2) ↑ serum and hepatic TG; (3) ↑ portal blood LPS; (4) ↑ CYP2E1 activity; and (5) ↓ ALT, TG, LPS (but not to basal levels) in EtOH-fed treated with RFX		(1) Lipid droplet accumulation in hepatic lobule; (2) Hepatomegaly; (3) ↑ 4-HNE; and (4) RFX counteractedthe aboveeffects	(1) ↑ ACCα, FASN; TNFα, IL-6, ILNγ; CCL-2; CD14, TLR-4, TLR-2; HMOX- 1, NOX-1; (2) ↓ CPT-1α; (3) ↑ CYP2E1 protein levels; no effect by RFX; and (4) RFX counteracted effects of EtOH on ACCα, FASN, TNFα, IFNγ, TLR-4, HMOX-1, and NOX-2, CPT-1α
Lazaro et al[81]	(1) Animal: Male WT and OPN- knockout C57BL/6 mice and (2) Diet: High-fat, high-cholesterol diet for 2 wk, then iG liquid HFD-EtOH (36% kcal from corn oil; 27 g/kg/d EtOH) or isocaloric HFD for 8 wk; Some HFD-EtOH given 4-5 g/kg/wk EtOH by gavage	(1) ↑ ALT, but ↓ with binge EtOH; ↓ ALT in binge-treated OPN KO compared to binge-treated WT; (2) ↑ bilirubin, ↓ albumin; (3) ↑ TG; and (4) No dif. in BAL		(1) Steatosis, hepatomegaly, mononuclear cell inflammation, neutrophil infiltration, perisinusoidal and percellular fibrosis in HFD-EtOH and (2) Splenomegaly, ↑ TLR-4 in binge-treated mice; effect of binge greater in OPN KO	(1) ↑ collagen I, αSMA, TIMP-1 by EtOH; further ↑ by EtOH binge; (2) ↑ myeloperoxidase, CXCL-1, OPN in binge-treated; and (3) ↑ myeloperoxidase, IL-17α in binge-treated OPN KO
Minato et al[96]	(1) Animal: 30 wk male OLET and OLETF rat; (2) Initial weight: 620 ± 15 g (OLETF), 460 ± 10 g (OLET); (3) Diet: 10 mL 10% EtOH by gavage for 1-5 d/wk; and (4) Duration: 3 wk	(1) ↑ ALT/AST; (2) ↑ serum and hepatic TG; (3) ↑ serum glucose; (4) ↑ serum insulin in OLETF, with no effect from EtOH; and (5) ↑ serum adiponectin in OLETF, ↓ by EtOH in OLETF		(1) Mild pericentral microvesicular steatosis in EtOH-naïve OLETF; (2) Steatohepatitis, focal hepatic necrosis, and hepatocyte ballooning in EtOH-treated OLETF; (3) ↑ hepatic CYP2E1; and (4) ↑ 4-ΗΝΕ	(1) ↑ PPARγ in OLETF, with no effect from EtOH and (2) ↑ TNFα
Nieto et al[85]	(1) Animal: 12 wk male Lewis rat; (2) Initial weight: 100 g; (3) Diet: Choline deficient (CD) diet; (4) 15 mL/kg whiskey by gavage 3 times per wk; and (5) Duration: 3 mo	(1) ↑ ALT/AST; (2) ↑ TG; (3) ↑ NEFA; (4) ↑ MDA, protein carbonyls; (5) ↑ serum TNFα, but ↓ in CD- whiskey; (6) ↑ CYP2E1 activity; (7) ↑ caspase-3, caspase-8 activity		(1) Minimal steatosis in whiskey-naïve CD rats and (2) Periportal and percentral microvesicular steatosis in CD-whiskey rats	(1) ↑ collagen 1, αSMA, cytochrome c, HSP47, CYP2E1; (2) ↑ leptin, TIMP-1, and BAX protein levels by CD, with no effect by whiskey; and (3) ↓ MMP-2, MMP-9, MMP-13, BCL-2, BCL-XL by CD, with no effect by whiskey
Osaki et al[101]	(1) Animal: Male Sprague-Dawley rat; (2) Initial weight: 106 g; (3) Diet: HFD (30% beef tallow, 20% casein, 20% sucrose); 1%-2% v/v EtOH ad libitum; and (4) Duration: 12 wk	(1) ↓ ALT; no dif. in AST; (2) ↓ ammonia, urate; (3) No dif. in serum glucose, FFA, cholesterol, HDL, bilirubin, alkaline phosphatase levels, urea, creatinine, lactate, acetate; (4) No dif. in hepatic TG, MDA; (5) No dif. in hepatic, renal, or pulmonary thiobarbituric acid-reactive substances		No dif. in hepatic TG, MDA No dif. in weight of liver, epididymal adipose tissue, perirenal adipose tissue, or gastrocnemius muscle	No dif. in TNFα, adiponectin, insulin-like growth factor binding protein 1, hemoglobin
Robin et al[86]	(1) Animal: Male ob/ob C57BL/6J mouse; (2) Initial weight: 49-56 g (obese), 26- 30 g (lean); (3) Diet: 2.5 g/kg/d EtOH by gastric intubation; (4) Drug: 100 mg/kg/d pentoxifylline (PTX) by iP; and (5) Duration: 4 d	(1) ↑ ALT in ob/ob; no effect by EtOH; (2) ↑ caspase-3,CYP2E1, SOD activities; ↓ caspase 3 by PTX; (3) ↓ GPx, cytosolic GT activity in ob/ob, but no effect by EtOH; (4) ↓ mitochondrial GT activity by EtOH; and (5) No dif. in GR activity		(1) Steatosis, caspase-3 activation in ob/ob; (2) TUNEL+ hepatocytes; and (3) Necrosis, inflammation in EtOH-naïve ob/ob	(1) ↑ TNFα protein levels; ↓ by PTX; (2) ↑ IκBα protein levels, ↓ NF-κB p65; ↓ NF-κB activity; (3) ↓ iNOS, BCL-XL; (4) ↓ cytosolic GSH, mitochondrial GSSG; and (5) ↑ HSP70
Song et al[124]	(1) Animal: 6 wk male C57BL/6J mouse; (2) Diet: high-fructose diet (20.2% kcal protein, 66.96% kcal carbohydrates, 12.9% kcal fat); 10% v/v EtOH for 2 d, 15% for 5 d, 20% for 17 wk; and (3) Duration: 18 wk	(1) ↑ ALT/AST; (2) ↑ plasma TG, NEFA, cholesterol by EtOH, but not fructose; (3) ↑ plasma glucose by fructose diet, ↓ glucose by EtOH; (4) ↑ insulin by fructose and EtOH, but not combined fructose-EtOH; (5) ↓ copper by fructose and EtOH, but not combined fructose-EtOH		(1) ↑ microvesicular steatosis and (2) ↑ macrovesicular steatosis in EtOH-naïve fructose; ↓ by fructose-EtOH diet	(1) ↑ hepatic CYP2E1 protein levels; (2) ↑ KHK in EtOH-naïve fructose; (3) ↑ F4/80, CD68, and TNFα, MyD88, IRF-3, and TRAF-6; (4) ↑ CCL-2, TLR-4, and IRF-7 only in fructose-EtOH; (5) ↑ CD163, IL-1β, or ARG-1 by EtOH, but no effect by fructose; and (6) No dif. in IL-6, IL-10
Sun et al[107]	(1) Animal: Male Sprague-Dawley rats; (2) Initial weight: 80-100 g; (3) Diet: HFD (38% fat, 2% cholesterol, 1% cholate) or control (38% kcal from fat); 4 g/kg/d EtOH by gavage beginning after 3 wk; and (4) Duration: 12 wk	No dif. in plasma LPS levels		(1) ↑ steatosis, fibrosis in HFD mice compared to HFD-EtOH and (2) ↑ Kupffer cell and HSC activation in HFD mice compared to HFD- EtOH	↑ inflammatory cytokines (TNFα, CXCL-1, CXCL-2, IL-1β, IL-6), pro- fibrotic markers (αSMA, collagen, TGF-β, TIMP-1, MMP-2, MMP-9) in HFD compared to HFD-EtOH
Suzuki et al[92]	(1) Animal: 8 wk male KK-Ay mouse; (2) Diet: LD containing 5% EtOH or isocaloric maltodextrin; 4 g/kg EtOH or isocaloric maltodextrin by gavage on day 11; (3) Drug: 120 mg/kg/d phenylbutyric acid (PBA); and (4) Duration: 10 d	(1) ↑ ALT/AST in chronic-binge mice; no dif. in ALT/AST between chronic-only and controls; (2) ↑ serum and hepatic TG; (3) No dif. in blood glucose; and (4) PBA ↓ ALT/AST, TG in EtOH-fed mice compared to PBA-naïve		(1) ↑ steatosis, PMN infiltration, ccCK18+ hepatocytes, 4-HNE+ cells in chronic-binge mice and (2) PBA alleviated liver injury, but did not decrease 4-HNE+ cell count	(1) ↑ inflammatory cytokines (TNFα, IL-6), ER stress markers (BiP, uXBP-1, sXBP-1, IP3R1, CHOP), and HMOX-1 by chronic-binge; PBA ↓ aforementioned genes; (2) ↑ BiP, uXBP-1 in chronic, but not sXBP-1, IP3R1, CHOP, HMOX-1; and (3) ↑ CYP2E1; PBA had no effect
Wang et al[78]	(1) Animal: 8 wk male Sprague-Dawley rat; (2) Diet: LD control (35% kcal from fat) or LD HFD (71% kcal from fat) for 6 wk; then LD HFD were given either solid HFD (55% kcal fat) or HF-EtOH diet (55% kcal fat, 16% kcal EtOH) for 4 wk; (3) Duration: 10 wk	(1) ↑ TUNEL+ hepatocytes; (2) ↑ cleaved caspase-3 levels; and (3) No dif. in 4-HNE or MDA levels between HFD and HFD-EtOH, but ↑ compared to controls		(1) Lipid droplet accumulation; (2) ↑ steatosis; and (3) ↑ number of inflammatory foci	(1) ↑ Fas death receptor and ligand; (2) No dif. in caspase-3 expression; (3) No dif. in CYP2E1, TNFα, TNFR-1, IL-1β, IL-12 between HFD and HFD-EtOH, but ↑ compared to controls
Xu et al[83]	(1) Animal: 8 wk male C57BL/6J mouse; (2) Diet: 580 kcal/kg/d (control) or 986 kcal/kg/d (overfed) of liquid HFD (37% kcal corn oil) by iG infusion for 45 d; 23 g/kg/d (low dose) or 32 g/kg/d (high dose) via iG infusion added to diet after 45; controls received isocaloric amount of diet; and (3) Duration: 10 wk	(1) ↑ hepatic TG, hepatic MDA, BAL in EtOH-treated overfed mice and (2) ↑ ALT in overfed mice; dose- dependent ↑ ALT by EtOH		(1) Steatosis, mononuclear cell infiltration in EtOH-treated (high dose) control mice; (2) Steatohepatitis and pericellular fibrosis in EtOH-treated (high dose) overfed mice; (3) ↑ macrophage infiltration in WAT in EtOH-treated overfed mice; and (4) No dif. in liver histology between EtOH-naïve overfed mice and controls	(1) ↑ M1 polarization markers (iNOS, TNFα) in liver and WAT for overfed-EtOH mice; (2) ↑ M2 markers (IL-10, ARG-1) in WAT, but ↓in liver for overfed- EtOH mice; (3) ↓ AdipoR, mitochondrial function genes (PGC-1α, PPARα, COX, cytochrome c, ACOX-1), in overfed-EtOH; (4) ↑ SREBP-1, ↓ pACC in EtOH; and (5) No effect on AMPK, PPARδ by overfeeding or EtOH

Results listed refer to experimental groups with concomitant metabolic syndrome risk factor and alcohol consumption compared to healthy or EtOH-naïve controls, unless stated otherwise. ACC: Acetyl-CoA carboxylase; ACOX: Acyl-CoA oxidase; AdipoR: Adiponectin receptor; ALT: Alanine aminotransferase; αSMA: Alpha smooth muscle actin; AUC: Area under the curve; ARG: Arginase; AST: Aspartate aminotransferase; BCL: B-cell lymphoma; BAX: BCL-2-associated X protein; BiP: Binding immunoglobulin protein; BAL: Blood alcohol level; CPT: Carnitine palmitoyltransferase; CHOP: C/EBP homologous protein; DGAT-2: Diacylglycerol O-acyltransferase 1; ER: Endoplasmic reticulum; EtOH: Ethanol; FA: Fatty acid; FASN: Fatty acid synthase; FAO: Fatty acid oxidation; FGF: Fibroblast growth factor; GTT: Glucose tolerance test; GSSG: Glutathione, oxidized; GSH: Glutathione, reduced; GPx: Glutathione peroxidases; GR: Glutathione reductase; GT: Glutathione transferase; H&E: Hematoxylin and eosin stain; HMOX: Heme oxygenase; HSP: Heat shock protein; HSC: Hepatic stellate cells; HCC: Hepatocellular carcinoma; HDL: High density lipoprotein; HFD: High-fat diet; HFHC: High-fat, high cholesterol diet; FFC: High-fat, high-fructose, high-cholesterol diet; 4-HNE: 4-hydroxynonenal; iNOS: Inducible nitric oxide synthase; IP3R1: Inositol trisphosphate receptor type 1; IR: Insulin receptor; IRS: Insulin receptor substrate; IFN: Interferon; IRF: Interferon regulatory factor; IL: Interleukin; iG: Intragastric; iP: Intraperitoneal; JNK: c-Jun N-terminal kinase; KHK: Ketohexokinase; LD: Lieber- DeCarli; LDL: Low density lipoprotein; MDA: Malondialdehyde; MMP: Matrix metallopeptidase; MCP: Monocyte chemoattractant protein; MUFA: Monounsaturated fatty acids; MyD88: Myeloid differentiation primary response 88; NOX: NADPH oxidase; NOX: NAFLD activity score; OLET: Otsuka Long-Evans Tokushima; OLETF: Otsuka Long-Evans Tokushima fatty; PLIN: Perilipin; PPAR: Peroxisome proliferator-activated receptor; PEPCK: Phosphoenolpyruvate carboxykinase; PAI-1: Plasminogen activator inhibitor 1; PUFA: Polyunsaturated fatty acids; PGC-1α: PPARγ coactivator 1 α; PHH: Primary human hepatocytes; Akt: Protein kinase B; SFA: Saturated fatty acids; SIRT-1: Sirtuin 1; SCD-1: Stearoyl-CoA desaturase 1; SREBP-1: Steroid response-element binding protein 1; SOD: Superoxide dismutase; TGFβ: Transforming growth factor β; TG: Triglycerides; TNFα: Tumor necrosis factor α; TRAF: TNF receptor associated factor; WAT: White adipose tissue; XBP-1: X-box binding protein 1.