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Nat Commun. 2018 Oct 26;9(1):4490. doi: 10.1038/s41467-018-06931-6.

Dietary cholesterol promotes steatohepatitis related hepatocellular carcinoma through dysregulated metabolism and calcium signaling.

Author information

1
Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Institute of Digestive Disease and Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
2
Liver Research Group, Australian National University Medical School at the Canberra Hospital, Garran, ACT, Australia.
3
Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China.
4
Department of Gastroenterology and Hepatology, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, WA, USA.
5
Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA.
6
Liver Research Group, Australian National University Medical School at the Canberra Hospital, Garran, ACT, Australia. geoff.farrell@anu.edu.au.
7
Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Institute of Digestive Disease and Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China. junyu@cuhk.edu.hk.

Abstract

The underlining mechanisms of dietary cholesterol and nonalcoholic steatohepatitis (NASH) in contributing to hepatocellular carcinoma (HCC) remain undefined. Here we demonstrated that high-fat-non-cholesterol-fed mice developed simple steatosis, whilst high-fat-high-cholesterol-fed mice developed NASH. Moreover, dietary cholesterol induced larger and more numerous NASH-HCCs than non-cholesterol-induced steatosis-HCCs in diethylnitrosamine-treated mice. NASH-HCCs displayed significantly more aberrant gene expression-enriched signaling pathways and more non-synonymous somatic mutations than steatosis-HCCs (335 ± 84/sample vs 43 ± 13/sample). Integrated genetic and expressional alterations in NASH-HCCs affected distinct genes pertinent to five pathways: calcium, insulin, cell adhesion, axon guidance and metabolism. Some of the novel aberrant gene expression, mutations and core oncogenic pathways identified in cholesterol-associated NASH-HCCs in mice were confirmed in human NASH-HCCs, which included metabolism-related genes (ALDH18A1, CAD, CHKA, POLD4, PSPH and SQLE) and recurrently mutated genes (RYR1, MTOR, SDK1, CACNA1H and RYR2). These findings add insights into the link of cholesterol to NASH and NASH-HCC and provide potential therapeutic targets.

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