title: Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease.
abstract: Nonalcoholic fatty liver disease (NAFLD) is associated with increased cardiovascular and liver-related mortality. NAFLD is characterized by both triglyceride and free cholesterol (FC) accumulation without a corresponding increment in cholesterol esters. The aim of this study was to evaluate the expression of cholesterol metabolic genes in NAFLD and relate these to disease phenotype. NAFLD was associated with increased SREBP-2 maturation, HMG CoA reductase (HMGCR) expression and decreased phosphorylation of HMGCR. Cholesterol synthesis was increased as measured by the circulating desmosterol:cholesterol ratio. miR-34a, a microRNA increased in NAFLD, inhibited sirtuin-1 with downstream dephosphorylation of AMP kinase and HMGCR. Cholesterol ester hydrolase was increased while ACAT-2 remained unchanged. LDL receptor expression was significantly decreased and similar in NAFLD subjects on or off statins. HMGCR expression was correlated with FC, histologic severity of NAFLD and LDL-cholesterol. These data demonstrate dysregulated cholesterol metabolism in NAFLD which may contribute to disease severity and cardiovascular risks.
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
authors.forename: Hae-Ki
authors.initials: HK
authors.lastname: Min
authors.forename: Ashwani
authors.initials: A
authors.lastname: Kapoor
authors.forename: Michael
authors.initials: M
authors.lastname: Fuchs
authors.forename: Faridoddin
authors.initials: F
authors.lastname: Mirshahi
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhou
authors.forename: James
authors.initials: J
authors.lastname: Maher
authors.forename: John
authors.initials: J
authors.lastname: Kellum
authors.forename: Russell
authors.initials: R
authors.lastname: Warnick
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Contos
authors.forename: Arun J
authors.initials: AJ
authors.lastname: Sanyal
mesh_terms: D000263:Adenylate Kinase / Q000235:genetics / Q000378:metabolism; D000328:Adult; D002318:Cardiovascular Diseases / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D002784:Cholesterol / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000235:genetics / Q000378:metabolism; D003897:Desmosterol / Q000097:blood / Q000378:metabolism; D005234:Fatty Liver / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics*; D008099:Liver / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease; D010641:Phenotype; D010766:Phosphorylation / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D002787:Sterol Esterase / Q000235:genetics / Q000378:metabolism; D002785:Sterol O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D000097587:Sterol O-Acyltransferase 2
chemical_list: D000263:Adenylate Kinase; D002784:Cholesterol; D008078:Cholesterol, LDL; D003897:Desmosterol; D006903:Hydroxymethylglutaryl CoA Reductases; D035683:MicroRNAs; D011973:Receptors, LDL; D056564:Sirtuin 1; D002787:Sterol Esterase; D002785:Sterol O-Acyltransferase; D051782:Sterol Regulatory Element Binding Protein 2; D000097587:Sterol O-Acyltransferase 2; C522425:MIRN34 microRNA, human; C497390:SREBF2 protein, human; C553220:HMGCR protein, human; C447939:SIRT1 protein, human