期刊
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
卷 307, 期 2, 页码 G164-G176出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00369.2013
关键词
fibrate; fatty acid; beta-oxidation; liver fatty acid-binding protein; hepatocyte
资金
- USPHS National Institutes of Health [DK41402, DK70965]
Although human liver fatty acid-binding protein (FABP1) T94A variant has been associated with nonalcoholic fatty liver disease and reduced ability of fenofibrate to lower serum triglycerides (TG) to target levels, molecular events leading to this phenotype are poorly understood. Cultured primary hepatocytes from female human subjects expressing the FABP1 T94A variant exhibited increased neutral lipid (TG, cholesteryl ester) accumulation associated with 1) upregulation of total FABP1, a key protein stimulating mitochondrial glycerol-3-phosphate acyltransferase (GPAM), the rate-limiting enzyme in lipogenesis; 2) increased mRNA expression of key enzymes in lipogenesis (GPAM, LPIN2) in heterozygotes; 3) decreased mRNA expression of microsomal triglyceride transfer protein; 4) increased secretion of ApoB100 but not TG; 5) decreased long-chain fatty acid (LCFA) beta-oxidation. TG accumulation was not due to any increase in LCFA uptake, de novo lipogenesis, or the alternate monoacylglycerol O-acyltransferase pathway in lipogenesis. Despite increased expression of total FABP1 mRNA and protein, fenofibrate-mediated FABP1 redistribution to nuclei and ligand-induced peroxisome proliferator-activated receptor (PPAR-alpha) transcription of LCFA beta-oxidative enzymes (carnitine palmitoyltransferase 1A, carnitine palmitoyltransferase 2, and acyl-coenzyme A oxidase 1, palmitoyl) were attenuated in FABP1 T94A hepatocytes. Although the phenotype of FABP1 T94A variant human hepatocytes exhibits some similarities to that of FABP1-null or PPAR-alpha-null hepatocytes and mice, expression of FABP1 T94A variant did not abolish or reduce ligand binding. Thus the FABP1 T94A variant represents an altered/reduced function mutation resulting in TG accumulation.
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