NAFLD-Related HCC: Focus on the Latest Relevant Preclinical Models

Abstract

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and one of the deadliest cancers worldwide. Despite extensive research, the biological mechanisms underlying HCC’s development and progression remain only partially understood. Chronic overeating and/or sedentary-lifestyle-associated obesity, which promote Non-Alcoholic Fatty Liver Disease (NAFLD), have recently emerged as worrying risk factors for HCC. NAFLD is characterized by excessive hepatocellular lipid accumulation (steatosis) and affects one quarter of the world’s population. Steatosis progresses in the more severe inflammatory form, Non-Alcoholic Steatohepatitis (NASH), potentially leading to HCC. The incidence of NASH is expected to increase by up to 56% over the next 10 years. Better diagnoses and the establishment of effective treatments for NAFLD and HCC will require improvements in our understanding of the fundamental mechanisms of the disease’s development. This review describes the pathogenesis of NAFLD and the mechanisms underlying the transition from NAFL/NASH to HCC. We also discuss a selection of appropriate preclinical models of NAFLD for research, from cellular models such as liver-on-a-chip models to in vivo models, focusing particularly on mouse models of dietary NAFLD-HCC.

The Influence of Diet and Its Components on the Development and Prevention of Hepatocellular Carcinoma (HCC)

“…Hepatocellular carcinoma (HCC) is a neoplasm whose development, beyond microbiological factors (HBV, HCV infections), depends on lifestyle choices, including dietary choices [ 1 ]. HCC develops as a consequence of chronic liver diseases characterized by inflammation and cirrhosis [ 2 ].…”

“…The development of cancer as a result of chronic metabolic abnormalities is attributed to recurring poor dietary choices, leading to excessive body weight, predisposing the individual to the accumulation of fat compounds in liver cells [ 1 ]. The accumulation of fat droplets in hepatocytes results in the development of non-alcoholic fatty liver disease [ 1 ]. Its progression may be accompanied by inflammation (non-alcoholic steatohepatitis), currently considered a major cause of mortality due to hepatocellular carcinoma [ 6 ].…”

Obesity under the moonlight of c-MYC

“…Altogether, excessive c-Myc overexpression only in hepatocytes alters the body’s metabolism and causes moderate obesity, spontaneous hyperlipidemia, glucose intolerance, and mild steatohepatitis/fibrosis ( Guo et al, 2021 ). Additionally, in various mouse MASLD ( Fang et al, 2023 ) and hepatocellular carcinoma (HCC) models, c-Myc-induced metabolic alterations further increase hepatocarcinogenesis ( Ma et al, 2000 ). In fact, this closely resembles human MASLD, where a combination of endogenous (such as oncogenes) and external (such as dietary habits) factors work together to promote the development of HCC.…”

Mannose Supplementation Curbs Liver Steatosis and Fibrosis in Murine MASH by Inhibiting Fructose Metabolism

“…mannose as a potential therapy for MASH in vivo, we used the well-validated FAT-MASH mouse model28-31 . Eight-week-old male C57BL/6J mice were given a high fat, high cholesterol, high sugar diet with liver triglycerides (TG), liver cholesterol, liver weight, and liver/body weight ratio compared to normal diet (ND) (Figures 1B-D, S1A-C).…”