Differential progression of unhealthy diet-induced hepatocellular carcinoma in obese and non-obese mice

Abstract

Background Non-alcoholic fatty liver disease (NAFLD) ranks first among liver diseases in Western countries. NAFLD is typically associated with obesity and diabetes, however it also develops in lean individuals without metabolic syndrome. The prevalence of lean NAFLD is 7 percent in the U.S. and 25–30 percent in some Asian countries. NAFLD starts with excess liver fat accumulation (NAFL), progresses to nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). The pathogenesis of lean NASH-HCC and how it differs from obese NASH-HCC is not well understood. Methods In this work, we generated a mouse model of lean and obese NASH-HCC using a choline deficient/high trans-fat/fructose/cholesterol diet and a choline supplemented/high trans-fat/fructose/cholesterol diet, respectively, to compare progression to NASH-HCC in lean versus obese mice. Comparisons were made at the organismal, histological, and molecular level by investigating fatty acid metabolism in the plasma of these mice. Results Obese mice showed more pronounced glucose intolerance and insulin resistance, higher levels of plasma cholesterol and triglycerides, and higher penetrance of NASH compared to lean mice. Despite the abnormal metabolic profile of obese mice, male obese and lean mice developed HCC with similar penetrance (53.3% and 53.8%, respectively), albeit lean mice showed faster tumor progression as evidenced by the larger tumor size and lower HCC-free survival. None of the female lean mice developed HCC, while 50% of female obese mice developed HCC. Both groups of mice showed a reduction in plasma polyunsaturated fatty acids (PUFAs), however, the levels were higher towards the endpoint in obese mice compared to lean mice. Conclusions Unhealthy diet composition appears to drive progression to NASH-HCC rather than the organismal effects of obesity. PUFA levels may increase due to systemic inflammation in obese mice and act as suppressors of tumor progression, thus delaying HCC progression in obese mice compared to lean mice. These models could be used to further dissect the molecular pathogenesis of lean and obese NASH-HCC and address the mechanisms whereby PUFAs may be implicated in hepatocarcinogenesis.

Differential methylation patterns in lean and obese non-alcoholic steatohepatitis-associated hepatocellular carcinoma

“…The increased number of DMRs and hypermethylation in the obese mice may be driven by dietary choline, which is involved in one-carbon metabolism in methylation [39]. Additionally, our previous work found that mice with HCC in the context of obesity had higher plasma fasting glucose and cholesterol levels than lean mice with HCC [40]; differences in glucose levels may contribute to the differential methylation patterns identified, which is in line with previous work that found glucose levels were associated with CpG methylation levels [41].…”

Relationship of Metabolic Dysfunction-associated Steatohepatitis-related Hepatocellular Carcinoma with Oral and Intestinal Microbiota: A Cross-Sectional Pilot Study

“…High-fat, high-glucose, and low-fiber Western diets are known to accelerate progression from MASH to MASH-HCC [40]. In addition, the Western diet increases the abundance of the genus Fusobacterium and decreases the abundance of the genus Roseburia in the intestine [41].…”

Sex difference in liver diseases: How preclinical models help to dissect the sex-related mechanisms sustaining NAFLD and hepatocellular carcinoma

“…At the endpoint (64 weeks of age), Hymel et al. 171 observed that tumor progression was faster in males. None of the female lean mice fed a CD-HFFC diet developed HCC (only dysplastic nodules were reported), while 50% of female obese mice fed a CS-HFFC diet developed HCC at the endpoint.…”

“… Hymel et al. 171 Hepatocyte-specific Pten-deficient mice (C57BL/6J background) at 40 weeks and 76 weeks Lower HCC incidence and smaller HCC size in females. Anezaki et al.…”