Liver fatty acid binding protein gene ablation potentiates hepatic cholesterol accumulation in cholesterol-fed female mice
ABSTRACT Although liver fatty acid binding protein (L-FABP) is postulated to influence cholesterol homeostasis, the physiological significance of this hypothesis remains to be resolved. This issue was addressed by examining the response of young (7 wk) female mice to L-FABP gene ablation and a cholesterol-rich diet. In control-fed mice, L-FABP gene ablation alone induced hepatic cholesterol accumulation (2.6-fold), increased bile acid levels, and increased body weight gain (primarily as fat tissue mass). In cholesterol-fed mice, L-FABP gene ablation further enhanced the hepatic accumulation of cholesterol (especially cholesterol ester, 12-fold) and potentiated the effects of dietary cholesterol on increased body weight gain, again mainly as fat tissue mass. However, in contrast to the effects of L-FABP gene ablation in control-fed mice, biliary levels of bile acids (as well as cholesterol and phospholipids) were reduced. These phenotypic alterations were not associated with differences in food intake. In conclusion, it was shown for the first time that L-FABP altered cholesterol metabolism and the response of female mice to dietary cholesterol. While the biliary and lipid phenotype of female wild-type L-FABP+/+ mice was sensitive to dietary cholesterol, L-FABP gene ablation dramatically enhanced many of the effects of dietary cholesterol to greatly induce hepatic cholesterol (primarily cholesterol ester) and triacylglycerol accumulation as well as to potentiate body weight gain (primarily as fat tissue mass). Taken together, these data support the hypothesis that L-FABP is involved in the physiological regulation of cholesterol metabolism, body weight gain, and obesity.
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ABSTRACT: Although human liver fatty acid binding protein (FABP1) T94A variant has been associated with non-alcoholic fatty liver disease (NAFLD) 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 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 (MTTP); 4) increased secretion of ApoB100 but not TG; 5) decreased LCFA β-oxidation. TG accumulation was not due to any increase in long chain fatty acid (LCFA) uptake, de novo lipogenesis, or the alternate MOGAT pathway in lipogenesis. Despite increased expression of total FABP1 mRNA and protein, fenofibrate mediated FABP1 redistribution to nuclei and ligand-induced PPARα transcription of LCFA β-oxidative enzymes (CPT1A, CPT2, and ACOX1) were attenuated in FABP1 T94A hepatocytes. While the phenotype of FABP1 T94A variant human hepatocytes exhibits some similarities to that of FABP1 null or PPARα 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.AJP Gastrointestinal and Liver Physiology 05/2014; 307(2). DOI:10.1152/ajpgi.00369.2013 · 3.74 Impact Factor
British Journal of Surgery 03/2013; 100(1):3. · 5.21 Impact Factor
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ABSTRACT: The purpose of this study was to evaluate the relation between the L-FABP T94A and MTP I128T polymorphisms and hyperlipidemia in Chinese subjects. We recruited 390 volunteers: 201 hyperlipidemic and 189 healthy volunteers. The L-FABP T94A and MTP I128T polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Anthropometry, lipid profile, and liver function of the subjects were determined. We observed that male carriers of the L-FABP A94 allele had significantly higher body weight (P = 0.012), higher body mass index (BMI) (P = 0.014), and higher plasma triacylglycerol levels (TAG) (P = 0.033) and lower ratios of high-density lipoprotein cholesterol (HDL-C) to total cholesterol (TC) (P = 0.008) than T94 homozygotes. The MTP T128 allele was associated with significantly lower serum TC (P < 0.001) and low-density lipoprotein cholesterol (LDL-C) (P < 0.001) levels in males. There was a direct correlation between the MTP T128 allele and a decreased risk of hyperlipidemia after adjusting for body mass index (OR = 0.327, 95 % CI: 0.178-0.600, P < 0.001). In conclusion, both the MTP I128T and the L-FABP T94A polymorphisms can affect serum lipid levels in the Chinese population. The MTP T128 allele offers protection against hyperlipidemia in the Chinese population.Lipids 02/2015; 50(3). DOI:10.1007/s11745-015-3990-3 · 2.35 Impact Factor