Nutritional model of steatohepatitis and metabolic syndrome ... : Hepatology (original) (raw)

Steatohepatitis/Metabolic Liver Disease

Nutritional model of steatohepatitis and metabolic syndrome in the Ossabaw miniature swine#

Lee, Lydia1; Alloosh, Mouhamad2; Saxena, Romil3; Van Alstine, William4; Watkins, Bruce A.5; Klaunig, James E.6; Sturek, Michael2; Chalasani, Naga1*†

1 Department of Medicine, Indiana University School of Medicine, Indianapolis, IN

2 Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN

3 Department of Pathology, Indiana University School of Medicine, Indianapolis, IN

4 Department of Comparative Pathobiology, Purdue University, West Lafayette, IN

5 Basic Medical Sciences, School of Veterinary Medicine, Purdue University, West Lafayette, IN

6 Department of Pharmacology, Indiana University School of Medicine, Indianapolis, IN

* Indiana University School of Medicine, RG 4100, 1050 Wishard Boulevard, Indianapolis, IN 46202

Email:[email protected]

Received December 23, 2008; accepted February 4, 2009.

Published online 11 February 2009 in Wiley InterScience (www.interscience.wiley.com).

Grant sponsor: Public Health Service; Grant Numbers: RR-013223 HL-062552; Grant sponsor: Purina TestDiet, Inc.; Grant Number: R01CA100908; Grant sponsor: Purdue-Indiana University Comparative Medicine Program.

# Potential conflict of interest: Nothing to report.

† fax: 317-278-1949

Additional Supporting Information may be found in the online version of this article.

Abstract

Miniature pigs residing in the Ossabaw Island (Ossabaw pigs) exhibit a thrifty genotype, and when fed a high-calorie diet they consistently develop metabolic syndrome defined by obesity, insulin resistance, hypertension, and dyslipidemia. We conducted a study to induce steatohepatitis in Ossabaw pigs by dietary manipulation. Pigs were fed standard chow (controls, n = 15), high-fructose diet (20% kcal from fructose and 10.5% kcal from fat) (fructose group, n = 9), atherogenic diet (20% kcal from fructose and 46% kcal from fat and 2% cholesterol and 0.7% cholate by weight) (atherogenic diet group, n = 13), and modified atherogenic diet (different source of fat and higher protein but lower choline content) (M-Ath diet group, n = 7). All animals were sacrificed at 24 weeks after dietary intervention. The high-fructose group had significant weight gain, hypertension, and insulin resistance but showed normal liver histology. The atherogenic diet group had metabolic syndrome and abnormal liver histology consisting of significant microvesicular steatosis and fatty Kupffer cells but no ballooning or fibrosis. The M-Ath diet group developed severe metabolic syndrome and markedly abnormal liver histology with macrovesicular and microvesicular steatosis, fatty Kupffer cells, extensive hepatocyte ballooning, and pericellular/perisinusoidal fibrosis. Compared with controls, the M-Ath diet group had significantly lower serum adiponectin but higher serum leptin and tumor necrosis factor (TNF) levels and higher hepatic triglyceride and malondialdehyde levels. Conclusion: Ossabaw pigs fed a modified atherogenic diet develop severe metabolic syndrome and abnormal liver histology with close resemblance to human nonalcoholic steatohepatitis (NASH). (Hepatology 2009.)