Synergistic interaction of dietary cholesterol and dietary... : Hepatology (original) (raw)

Steatohepatitis/Metabolic Liver Disease

Synergistic interaction of dietary cholesterol and dietary fat in inducing experimental steatohepatitis

Savard, Christopher1,2; Tartaglione, Erica V.1; Kuver, Rahul2; Haigh, Geoffrey W.1; Farrell, Geoffrey C.3; Subramanian, Savitha4; Chait, Alan4; Yeh, Matthew M.5; Quinn, LeBris S.6; Ioannou, George N.1,2,*,9

1Research Enhancement Award Program, Veterans Affairs Puget Sound Health Care System, Seattle, WA

2Division of Gastroenterology, University of Washington, Seattle, WA

3Liver Research Group, Austrailian National University Medical School at The Canberra Hospital, Garran, Australian Capital Territory, Australia

4Division of Metabolism, Endocrinology and Nutrition and Diabetes Obesity Center for Excellence, University of Washington, Seattle, WA

5Department of Pathology, University of Washington, Seattle, WA

6Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA

*Division of Gastroenterology, Veterans Affairs Puget Sound Health Care System, S-111-Gastro, 1660 South Columbian Way, Seattle, WA 98108

Email: [email protected]

Received 6 January 2012; Accepted 10 April 2012

8Potential conflict of interest: Nothing to report.

7This work was supported by the Research Enhancement Award Program (to G.N.I.), Office of Research and Development, Veterans Affairs.

9fax: 206-764-2232

Abstract

The majority of patients with nonalcoholic fatty liver disease (NAFLD) have “simple steatosis,” which is defined by hepatic steatosis in the absence of substantial inflammation or fibrosis and is considered to be benign. However, 10%-30% of patients with NAFLD progress to fibrosing nonalcoholic steatohepatitis (NASH), which is characterized by varying degrees of hepatic inflammation and fibrosis, in addition to hepatic steatosis, and can lead to cirrhosis. The cause(s) of progression to fibrosing steatohepatitis are unclear. We aimed to test the relative contributions of dietary fat and dietary cholesterol and their interaction on the development of NASH. We assigned C57BL/6J mice to four diets for 30 weeks: control (4% fat and 0% cholesterol); high cholesterol (HC; 4% fat and 1% cholesterol); high fat (HF; 15% fat and 0% cholesterol); and high fat, high cholesterol (HFHC; 15% fat and 1% cholesterol). The HF and HC diets led to increased hepatic fat deposition with little inflammation and no fibrosis (i.e., simple hepatic steatosis). However, the HFHC diet led to significantly more profound hepatic steatosis, substantial inflammation, and perisinusoidal fibrosis (i.e., steatohepatitis), associated with adipose tissue inflammation and a reduction in plasma adiponectin levels. In addition, the HFHC diet led to other features of human NASH, including hypercholesterolemia and obesity. Hepatic and metabolic effects induced by dietary fat and cholesterol together were more than twice as great as the sum of the separate effects of each dietary component alone, demonstrating significant positive interaction. Conclusion: Dietary fat and dietary cholesterol interact synergistically to induce the metabolic and hepatic features of NASH, whereas neither factor alone is sufficient to cause NASH in mice. (Hepatology 2013)

Abbreviations:Abc, ATP-binding cassette transporter; Acat2, acylCo:cholesterol acyltransferase 2; ALT, alanine aminotransferase; Cpt-1a, carnitine palmitoyl trasferase 1 alpha; Cyp, cytochrome P450; ELSD, evaporative light-scattering detection; FFAs, free fatty acids; HF, high-fat diet; HC, high-cholesterol diet; HFHC, high-fat and high-cholesterol diet; Hmg, 3-hydroxy-3-methylglutaryl-coenzyme A; HMW, high molecular weight; HPLC, high-performance liquid chromatography; IL, interleukin; IR, insulin resistance; KO, knockout; MMP, matrix metalloproteinases; mRNA, messenger RNA; Mttp, microsomal triglyceride transfer protein; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; _Ppar_α, peroxisome proliferator receptor α; RT-PCR, reverse-transcription polymerase chain reaction; SD, standard deviation; TNF-α, tumor necrosis factor alpha; VLDL, very-low-density lipoprotein.