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Alcohol Induces Angiopoeitin like‐3 (ANGPTL3) in the Liver: Implications for Alcohol Induced Hypertriglyceridemia
Author(s) -
Sadana Prabodh,
Burke Jamie,
Jogasuria Alvin,
Darvesh Altaf,
Geldenhuys Werner,
Wu Jiashin,
You Min
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.885.21
Subject(s) - hypertriglyceridemia , endocrinology , medicine , sirtuin 1 , lipoprotein lipase , fatty liver , alcoholic liver disease , chylomicron , lipid metabolism , lipoprotein , chemistry , biology , biochemistry , cholesterol , gene , very low density lipoprotein , downregulation and upregulation , triglyceride , disease , cirrhosis , adipose tissue
Elevated triglycerides (TGs) are an independent risk factor for cardiovascular disease (CVD). Lipoprotein lipase (LPL) found along the capillary endothelium catalyzes the hydrolysis of TG rich lipoproteins and chylomicrons. Angiopoietin‐like (ANGPTL) proteins including ANGPTL3 have been identified as endogenous inhibitors of LPL. As a result, ANGPTL3 overexpression is associated with elevated TGs and increased risk for CVD. Excessive alcohol intake is associated with secondary hypertriglyceridemia and may worsen the hypertriglyceridemia seen in primary lipid disorders. We investigated whether ANGPTL3 is an alcohol target gene. In mice chronic‐binge model of alcohol feeding, an induction of ANGPTL3 protein was observed in the liver, a primary site of ANGPTL3 expression. Further, in mouse hepatocyte cell line AML12 similar induction of ANGPTL3 protein was observed. Interestingly, alcohol failed to induce ANGPTL3 mRNA expression. Similarly, no effect of alcohol was observed on 1kb 5' ANGPTL3 flanking sequence driven luciferase reporter gene. Sirtuin‐1 (SIRT1) plays a central role in mediating the effects of ethanol on hepatic lipid metabolism and development of alcoholic fatty liver. SIRT1 activation and overexpression was observed to inhibit the expression of hepatic ANGPTL3 protein and luciferase reporter respectively. However, ethanol retained the ability to induce ANGPTL3 protein in SIRT1 knockout mice. In summary, hepatic ANGPTL3 is induced by ethanol and such regulation does not involve changes in ANGPTL3 gene transcription or a role of SIRT1. Regulation of ANGPTL3 offers a mechanistic explanation for plasma TG elevation upon chronic alcohol intake.