title: Dietary cholesterol exacerbates hepatic steatosis and inflammation in obese LDL receptor-deficient mice.
abstract: 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.
authors.affiliation: Diabetes and Obesity Center of Excellence, University of Washington, Seattle, WA, USA.
authors.forename: Savitha
authors.initials: S
authors.lastname: Subramanian
authors.forename: Leela
authors.initials: L
authors.lastname: Goodspeed
authors.forename: Shari
authors.initials: S
authors.lastname: Wang
authors.forename: Jinkyu
authors.initials: J
authors.lastname: Kim
authors.forename: Lixia
authors.initials: L
authors.lastname: Zeng
authors.forename: George N
authors.initials: GN
authors.lastname: Ioannou
authors.forename: W Geoffrey
authors.initials: WG
authors.lastname: Haigh
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Yeh
authors.forename: Kris V
authors.initials: KV
authors.lastname: Kowdley
authors.forename: Kevin D
authors.initials: KD
authors.lastname: O'Brien
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Pennathur
authors.forename: Alan
authors.initials: A
authors.lastname: Chait
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002791:Cholesterol, Dietary / Q000009:adverse effects* / Q000378:metabolism; D004032:Diet; D018450:Disease Progression; D005234:Fatty Liver / Q000150:complications / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007249:Inflammation / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D065626:Non-alcoholic Fatty Liver Disease; D009765:Obesity / Q000473:pathology / Q000503:physiopathology; D018384:Oxidative Stress; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics
chemical_list: D002791:Cholesterol, Dietary; D011973:Receptors, LDL