title: Electronegative LDL is linked to high-fat, high-cholesterol diet-induced nonalcoholic steatohepatitis in hamsters.
abstract: The pathogenesis of nonalcoholic steatohepatitis (NASH), like that of atherosclerosis, involves lipid accumulation, inflammation and fibrosis. Recent studies suggest that oxidized LDL (oxLDL) may be a risk factor for NASH, but oxLDL levels were not directly measured in these studies. The aim of this study was to examine whether there was an association between electronegative LDL [LDL(-)], a mildly oxLDL found in the blood, and the development of NASH using two animal models. Golden Syrian hamsters and C57BL/6 mice were fed a high-fat, high-cholesterol (HFC) diet for 6 or 12weeks, then liver lipid and histopathology, plasma lipoprotein profile and LDL(-) levels were examined. The HFC-diet-fed hamsters and mice had similar levels of hepatic lipid but different histopathological changes, with microvesicular steatosis, hepatocellular hypertrophy, inflammation and bridging fibrosis in the hamsters, but only in mild steatohepatitis with low inflammatory cell infiltration in the mice. It also resulted in a significant increase in plasma levels of LDL cholesterol and LDL(-) in hamsters, but only a slight increase in mice. Moreover, enlarged Kupffer cells, LDL(-) and accumulation of unesterified cholesterol were detected in the portal area of HFC-diet-fed hamsters, but not HFC-diet-fed mice. An in vitro study showed that LDL(-) from HFC-diet-fed hamsters induced TNF-α secretion in rat Kupffer cell through a LOX-1-dependent pathway. Our results strongly suggest that LDL(-) is one of the underlying causes of hepatic inflammation and plays a critical role in the development of NASH.
authors.affiliation: Department of Biochemistry and Molecular Biology, National Taiwan University, Taipei, Taiwan.
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Lai
authors.affiliation: Department of Biochemistry and Molecular Biology, National Taiwan University, Taipei, Taiwan.
authors.forename: Tzu-Ching
authors.initials: TC
authors.lastname: Yang
authors.affiliation: Department of Internal Medicine, College of Medicine, National Taiwan University,Taipei,Taiwan.
authors.forename: Po-Yuan
authors.initials: PY
authors.lastname: Chang
authors.affiliation: Graduate Institute of Cell and Molecular Biology, Taipei Medical University,Taipei,Taiwan.
authors.forename: Shwu-Fen
authors.initials: SF
authors.lastname: Chang
authors.affiliation: Hepatitis Research Center, National Taiwan University Hospital,Taipei,Taiwan.
authors.forename: Shu-Li
authors.initials: SL
authors.lastname: Ho
authors.affiliation: Hepatitis Research Center, National Taiwan University Hospital,Taipei,Taiwan. Electronic address: hlchen9@ntu.edu.tw.
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, National Taiwan University, Taipei, Taiwan. Electronic address: lsc@ntu.edu.tw.
authors.forename: Shao-Chun
authors.initials: SC
authors.lastname: Lu
mesh_terms: D000818:Animals; D002791:Cholesterol, Dietary / Q000008:administration & dosage*; D006224:Cricetinae; D059305:Diet, High-Fat; D008077:Lipoproteins, LDL / Q000008:administration & dosage*; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology*
chemical_list: D002791:Cholesterol, Dietary; D008077:Lipoproteins, LDL
keywords: Electronegative LDL (LDL(−)); Hamster; Hepatic inflammation; Lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1); Nonalcoholic steatohepatitis (NASH)