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Human FABP1 T94A Variant Impacts Fatty Acid Metabolism and PPAR-α Activation in Cultured Human Female Hepatocytes

Human FABP1 T94A Variant Impacts Fatty Acid Metabolism and PPAR-α Activation in Cultured Human Female Hepatocytes

Avery L McIntosh, Huan Huang, Stephen M Storey, Kerstin K Landrock, Danilo Landrock, Anca D Petrescu, Shipra Gupta, Barbara P Atshaves, Ann B Kier, Friedhelm Schroeder

Am J Physiol Gastrointest Liver Physiol. 2014 Jul 15;307(2):G164-76.

PMID: 24875102

Abstract:

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) β-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-α) transcription of LCFA β-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-α-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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4247102	FABP1 human			Price

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