title: Cholesterol-lowering drugs cause dissolution of cholesterol crystals and disperse Kupffer cell crown-like structures during resolution of NASH.
abstract: Cholesterol crystals form within hepatocyte lipid droplets in human and experimental nonalcoholic steatohepatitis (NASH) and are the focus of crown-like structures (CLSs) of activated Kupffer cells (KCs). Obese, diabetic Alms1 mutant (foz/foz) mice were a fed high-fat (23%) diet containing 0.2% cholesterol for 16 weeks and then assigned to four intervention groups for 8 weeks: a) vehicle control, b) ezetimibe (5 mg/kg/day), c) atorvastatin (20 mg/kg/day), or d) ezetimibe and atorvastatin. Livers of vehicle-treated mice developed fibrosing NASH with abundant cholesterol crystallization within lipid droplets calculated to extend over 3.3% (SD, 2.2%) of liver surface area. Hepatocyte lipid droplets with prominent cholesterol crystallization were surrounded by TNFα-positive (activated) KCs forming CLSs (≥ 3 per high-power field). KCs that formed CLSs stained positive for NLRP3, implicating activation of the NLRP3 inflammasome in response to cholesterol crystals. In contrast, foz/foz mice treated with ezetimibe and atorvastatin showed near-complete resolution of cholesterol crystals [0.01% (SD, 0.02%) of surface area] and CLSs (0 per high-power field), with amelioration of fibrotic NASH. Ezetimibe or atorvastatin alone had intermediate effects on cholesterol crystallization, CLSs, and NASH. These findings are consistent with a causative link between exposure of hepatocytes and KCs to cholesterol crystals and with the development of NASH possibly mediated by NLRP3 activation.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, WA.
authors.forename: George N
authors.initials: GN
authors.lastname: Ioannou
authors.affiliation: Liver Research Group, Australian National University Medical School at the Canberra Hospital, Garran, ACT, Australia.
authors.forename: Derrick M
authors.initials: DM
authors.lastname: Van Rooyen
authors.affiliation: Division of Gastroenterology, Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, WA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Savard
authors.affiliation: Division of Gastroenterology, Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, WA.
authors.forename: W Geoffrey
authors.initials: WG
authors.lastname: Haigh
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Yeh
authors.affiliation: Liver Research Group, Australian National University Medical School at the Canberra Hospital, Garran, ACT, Australia.
authors.forename: Narci C
authors.initials: NC
authors.lastname: Teoh
authors.affiliation: Liver Research Group, Australian National University Medical School at the Canberra Hospital, Garran, ACT, Australia.
authors.forename: Geoffrey C
authors.initials: GC
authors.lastname: Farrell
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000069059:Atorvastatin; D001384:Azetidines / Q000494:pharmacology / Q000627:therapeutic use; D002784:Cholesterol / Q000378:metabolism*; D000069438:Ezetimibe; D005260:Female; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use; D058847:Inflammasomes / Q000187:drug effects / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects* / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000924:Anticholesteremic Agents; D001384:Azetidines; D006538:Heptanoic Acids; D058847:Inflammasomes; D011758:Pyrroles; D002784:Cholesterol; D000069059:Atorvastatin; D000069438:Ezetimibe
keywords: caspase 1; crown-like structure; lipotoxicity; nonalcoholic steatohepatitis