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Liu et al. Hepatoma Res 2020;6:7 I http://dx.doi.org/10.20517/2394-5079.2019.39 Page 7 of 16

Increased size and multiplicity in HFHC- fed mice compared with HFD-fed mice WG, IR, steatosis and inflammation present Median diameter of tumours = 9 mm WG, IR, steatosis, inflammation and fibrosis present Weight loss, steatosis, inflammation and fibrosis present WG, diabetes (no IR), steatosis, inflammation and fibrosis present Insulin hypersensitivity, steatosis and inflammation but no fibrosis present Other examples of single gene knockout

At 8 months, tumours displayed in: HFD 90% HFHC 100% 30% displayed tumours at 6 months 100% displayed tumours at 9 months 83% displayed tumours at 24 weeks 100% displayed tumours at 20 weeks. No female mice developed tumours At 74-78 weeks, tumours displayed in: Males 66% Females 30% 100% displayed tumours at 9 months 78.6% displayed had tumours > 2 mm, and 35.7% displayed tumours > 10 mm fibrosis present at 40 weeks 4/13 (30.7%

DEN 25 mg/kg i.p. single dose at Week CCl 4 0.2 µL/g i.p. weekly from Weeks DEN 25 mg/kg i.p. single dose at Day 14 TAA 300 mg/L in drinking water from Week 4 DEN 25 mg/kg i.p. single dose at Week DEN 25 mg/kg i.p. single dose at Day 15 *List of models presented are not intended to be exhaustive but to give representative examples of different combinations of methods to achieve hepatocarcinogenesis in alcoholic and metabolic liver diseases. AFP

HFD or HFHC 3 from 6 weeks CDAA from 6-8 Weeks 6-8 HFD from Week 4 HFD from Week 4 STZ 200 µg s.c. at Day 2 - - - 2 HFD from Week 6 - - Added 10 mg ferrous sulphate/ kg normal chow from 8-15 months for 6-8 months -

Hepatocyte- specific PTEN knockout: AlbCrePten flox/ deficient genetically obese (Ob) MUP-uPA transgene microglobulin knockout Hepatocyte specific FBXL5 knockout: Alb- Cre/Fbxl5 flox/ flox mice stelic animal model; STZ: streptozotocin; TAA: thioacetamide; WD: Western diet; WG: weight gain

- - - - flox Leptin β2-
C57BL/6J male C57BL/6J male C57BL/6J male C57BL/6 male and female C57BL/6J male and female C57BL/6J male C57BL/6 male C57BL/6 male and female C57BL/6 male and female

HFHC + DEN Liang et al. [63] CDAA + CCl 4 De Minicis et al. [56] HFD + DEN + CCl 4 Henderson et al. [64] STAM Fujii et al. [66] PTEN knockout Horie et al. [28] Leptin deficiency (Ob) + DEN Park et al. [62] MUP-uPA Nakagawa et al. [71] Haemochromatosis HCC models β2-microglobulin knockout Rothenberg et al. [76] FBXL5 knockout Muto et al. [77]