Diet-induced hepatocellular carcinoma in genetically predisposed mice

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide, with approximately 70% of cases resulting from hepatitis B and C viral infections, aflatoxin exposure, chronic alcohol use or genetic liver diseases. The remaining approximately 30% of cases are associated with obesity, type 2 diabetes and related metabolic diseases, although a direct link between these pathologies and HCCs has not been established. We tested the long-term effects of high-fat and low-fat diets on males of two inbred strains of mice and discovered that C57BL/6J but not A/J males were susceptible to non-alcoholic steatohepatitis (NASH) and HCC on a high-fat but not low-fat diet. This strain-diet interaction represents an important model for genetically controlled, diet-induced HCC. Susceptible mice showed morphological characteristics of NASH (steatosis, hepatitis, fibrosis and cirrhosis), dysplasia and HCC. mRNA profiles of HCCs versus tumor-free liver showed involvement of two signaling networks, one centered on Myc and the other on NFkappaB, similar to signaling described for the two major classes of HCC in humans. miRNA profiles revealed dramatically increased expression of a cluster of miRNAs on the X chromosome without amplification of the chromosomal segment. A switch from high-fat to low-fat diet reversed these outcomes, with switched C57BL/6J males being lean rather than obese and without evidence for NASH or HCCs at the end of the study. A similar diet modification may have important implications for prevention of HCCs in humans.

Persistent Chromatin Modifications Induced by High Fat Diet*

“…To investigate the genetic component of the persistence of diet-induced changes in chromatin accessibility, we chose to examine A/J mice, a strain of mice known to display differences in metabolic dysfunction under HF diet as compared with B6 mice (14). A/J mice placed on a HF diet for 16 weeks or those fed 8 weeks of HF diet followed by 8 weeks of control diet (reversal) do not gain more weight than those fed a control diet for 16 weeks (Fig.…”

“…Furthermore, loci of persistent chromatin accessibility changes are associated with transcriptional regulation of important metabolic genes. We further investigated chromatin accessibility with the same diet scheme in A/J mice, which are known to display metabolic differences under HF diet as compared with B6 mice (14). Chromatin accessibility changes under HF diet feeding do occur in these mice, but the vast majority of the chromatin changes are reversible by the dietary changes.…”

Western diet in ApoE-LDLR double-deficient mouse model of atherosclerosis leads to hepatic steatosis, fibrosis, and tumorigenesis

“…Further, the dietary-induced onset of NAFLD-associated tumors in AL mice on WD in our study is considerably faster than that reported previously in related mouse models. 34 ROS accumulation promotes cell death through various mechanisms, including prolonged JNK activation. 35 In the current study, both ROS accumulation and prolonged JNK activation, in combination with enhanced hepatocellular injury, might drive tumorigenesis.…”

From Peas to Disease: Modifier Genes, Network Resilience, and the Genetics of Health

“…C57BL/6J but not A/J mice develop obesity, insulin resistance, hepatic steatosis, and liver cancer when fed a diet high in saturated fat. 50,51 Genome surveys using a panel of chromosome substitution strains (CSSs) in which each C57BL/6J chromosome has been individually replaced with the corresponding A/J chromosome 52 showed that sequence variants on many chromosomes control susceptibility, with the effects of each acting in a highly non-additive manner. 53,54 For the majority of traits, the cumulative phenotypic effect (sum of the signed deviation from C57BL/6J) across all strains in the CSS panel was found to greatly exceed 100%, with an average cumulative effect of $800% across 90 blood, bone, and metabolic traits.…”