期刊
JOURNAL OF LIPID RESEARCH
卷 52, 期 9, 页码 1626-1635出版社
ELSEVIER
DOI: 10.1194/jlr.M016246
关键词
fatty liver; metabolic syndrome; oxysterols; apoptosis; oxidative stress; low density lipoprotein; oxidized fatty acids
资金
- National Institutes of Health [P30 DK-035816, P01 HL-092969, DK-082841, DK-089503]
- mentor-based American Diabetes Association
Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, can progress to steatohepatitis (NASH) and advanced liver disease. Mechanisms that underlie this progression remain poorly understood, partly due to lack of good animal models that resemble human NASH. We previously showed that several metabolic syndrome features that develop in LDL receptor-deficient (LDLR-/-) mice fed a diabetogenic diet are worsened by dietary cholesterol. To test whether dietary cholesterol can alter the hepatic phenotype in the metabolic syndrome, we fed LDLR-/- mice a high-fat, high-carbohydrate diabetogenic diet (DD) without or with added cholesterol (DDC). Both groups of mice developed obesity and insulin resistance. Hyperinsulinemia, dyslipidemia, hepatic triglyceride, and alanine aminotransferase (ALT) elevations were greater with DDC. Livers of DD-fed mice showed histological changes resembling NAFLD, including steatosis and modest fibrotic changes; however, DDC-fed animals developed micro-and macrovesicular steatosis, inflammatory cell foci, and fibrosis resembling human NASH. Dietary cholesterol also exacerbated hepatic macrophage infiltration, apoptosis, and oxidative stress. Thus, LDLR-/- mice fed diabetogenic diets may be useful models for studying human NASH. Dietary cholesterol appears to confer a second hit that results in a distinct hepatic phenotype characterized by increased inflammation and oxidative stress.-Subramanian, S., L. Goodspeed, S. Wang, J. Kim, L. Zeng, G. N. Ioannou, W. G. Haigh, M. M. Yeh, K. V. Kowdley, K. D. O'Brien, S. Pennathur, and A. Chait. Dietary cholesterol exacerbates hepatic steatosis and inflammation in obese LDL receptor-deficient mice. J. Lipid Res. 2011. 52: 1626-1635.
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