title: APOC3 Protein Is Not a Predisposing Factor for Fat-induced Nonalcoholic Fatty Liver Disease in Mice.
abstract: Nonalcoholic fatty liver disease (NAFLD), characterized by excessive fat accumulation in liver, is prevalent in obesity. Genetic factors that link obesity to NAFLD remain obscure. Apolipoprotein C3 (APOC3) is a lipid-binding protein with a pivotal role in triglyceride metabolism. Humans with APOC3 gain-of-function mutations and mice with APOC3 overproduction are associated with hypertriglyceridemia. Nonetheless, it remains controversial whether APOC3 is culpable for diet-induced NAFLD. To address this fundamental issue, we fed APOC3-transgenic and wild-type littermates a high fructose diet or high fat diet, followed by determination of the effect of APOC3 on hepatic lipid metabolism and inflammation and the progression of NAFLD. To gain mechanistic insight into NAFLD, we determined the impact of APOC3 on hepatic triglyceride synthesis and secretionversusfatty acid oxidation. APOC3-transgenic mice were hypertriglyceridemic, culminating in marked elevation of triglycerides, cholesterols, and non-esterified fatty acids in plasma. Despite the prevailing hypertriglyceridemia, APOC3-transgenic mice, relative to wild-type littermates, had similar weight gain and hepatic lipid content without alterations in hepatic expression of key genes involved in triglyceride synthesis and secretion and fatty acid oxidation. APOC3-transgenic and wild-type mice had similar Kupffer cell content without alterations in hepatic expression of pro- and anti-inflammatory cytokines. APOC3 neither exacerbated diet-induced adiposity nor aggravated the degree of steatosis in high fructose or high fat-fed APOC3-transgenic mice. These effects ensued independently of weight gain even after 10-month high fat feeding. We concluded that APOC3, whose dysregulation is liable for hypertriglyceridemia, is not a predisposing factor for linking overnutrition to NAFLD in obesity.
authors.affiliation: From the Department of Endocrinology and Metabolism, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai 200072, China and.|the Division of Endocrinology and Diabetes, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Cheng
authors.affiliation: the Division of Endocrinology and Diabetes, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.
authors.forename: Jun
authors.initials: J
authors.lastname: Yamauchi
authors.affiliation: the Division of Endocrinology and Diabetes, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.
authors.forename: Sojin
authors.initials: S
authors.lastname: Lee
authors.affiliation: the Division of Endocrinology and Diabetes, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: the Division of Endocrinology and Diabetes, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Gong
authors.affiliation: the Division of Endocrinology and Diabetes, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.
authors.forename: Radhika
authors.initials: R
authors.lastname: Muzumdar
authors.affiliation: From the Department of Endocrinology and Metabolism, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai 200072, China and qushencn@hotmail.com.
authors.forename: Shen
authors.initials: S
authors.lastname: Qu
authors.affiliation: the Division of Endocrinology and Diabetes, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224 dongh@pitt.edu.
authors.forename: H Henry
authors.initials: HH
authors.lastname: Dong
mesh_terms: D000818:Animals; D053305:Apolipoprotein C-III / Q000235:genetics* / Q000378:metabolism*; D001835:Body Weight; D002784:Cholesterol / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D059305:Diet, High-Fat; D005260:Female; D005632:Fructose / Q000737:chemistry; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D005951:Glucose Tolerance Test; D015228:Hypertriglyceridemia / Q000378:metabolism; D007249:Inflammation; D007333:Insulin Resistance / Q000235:genetics; D050356:Lipid Metabolism / Q000187:drug effects; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism; D011401:Promoter Regions, Genetic; D019076:Transgenes; D014280:Triglycerides / Q000378:metabolism; D015430:Weight Gain
chemical_list: D053305:Apolipoprotein C-III; D016207:Cytokines; D008055:Lipids; D014280:Triglycerides; D005632:Fructose; D002784:Cholesterol
keywords: Apolipoprotein C3; Hypertriglyceridemia; Nonalcoholic fatty liver disease; Steatosis; Triglyceride metabolism; apolipoprotein; lipid metabolism; liver; obesity; triglyceride