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

Jessie Qiaoyi Liang, Narcissus Teoh, Lixia Xu, Sharon Pok, Xiangchun Li, Eagle S. H. Chu, Jonathan Chiu, Ling Dong, Evi Arfianti, W. Geoffrey Haigh, Matthew M. Yeh, George N. Ioannou, Joseph J. Y. Sung, Geoffrey Farrell () and Jun Yu ()
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Jessie Qiaoyi Liang: Institute of Digestive Disease and Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong
Narcissus Teoh: Australian National University Medical School at the Canberra Hospital
Lixia Xu: Institute of Digestive Disease and Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong
Sharon Pok: Australian National University Medical School at the Canberra Hospital
Xiangchun Li: Institute of Digestive Disease and Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong
Eagle S. H. Chu: Institute of Digestive Disease and Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong
Jonathan Chiu: Institute of Digestive Disease and Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong
Ling Dong: Zhongshan Hospital of Fudan University
Evi Arfianti: Australian National University Medical School at the Canberra Hospital
W. Geoffrey Haigh: Veterans Affairs Puget Sound Health Care System and University of Washington
Matthew M. Yeh: University of Washington School of Medicine
George N. Ioannou: Veterans Affairs Puget Sound Health Care System and University of Washington
Joseph J. Y. Sung: Institute of Digestive Disease and Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong
Geoffrey Farrell: Australian National University Medical School at the Canberra Hospital
Jun Yu: Institute of Digestive Disease and Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06931-6

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