Liver fatty acid binding protein gene ablation potentiates hepatic cholesterol accumulation in cholesterol-fed female mice

Deptarment of Physiology and Pharmacology, Texas A&M University, College Station, TX 77843-4467, USA.
AJP Gastrointestinal and Liver Physiology (Impact Factor: 3.8). 02/2006; 290(1):G36-48. DOI: 10.1152/ajpgi.00510.2004
Source: PubMed


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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    • "Despite these advances, interpretation of studies with SCP-2/ SCP-x gene-ablated mice has been complicated by concomitant upregulation [36] [37] [47] or downregulation [48] of liver fatty acid binding protein (L-FABP) as well as sex-differences in response. For example, mice exhibit sex-related differences in metabolism of branched-chain lipids [49], in hepatic regulation of cholesterol metabolism [50], in the hepatic lipid accumulation in mice lacking the L-FABP gene product only [22], as well as the response to a high-cholesterol diet in L-FABP gene-ablated mice [20] [51] To better resolve the impact of these proteins on hepatobiliary bile acid metabolism in female mice, studies were undertaken comparing female mice singly ablated in L-FABP (LKO), singly ablated in SCP-2/ SCP-x (DKO), or ablated in both L-FABP and SCP-2/SCP-x (TKO). The data herein demonstrate that L-FABP had a much greater impact on hepatic retention of bile acids while SCP-2/SCP-x more broadly affected biliary bile acid and phospholipid levels. "
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    ABSTRACT: Both sterol carrier protein-2/sterol carrier protein-x (SCP-2/SCP-x) and liver fatty acid binding protein (L-FABP) have been proposed to function in hepatobiliary bile acid metabolism/accumulation. To begin to address this issue, the impact of ablating L-FABP (LKO) or SCP-2/SCP-x (DKO) individually or both together (TKO) was examined in female mice. Biliary bile acid levels were decreased in LKO, DKO, and TKO mice; however, hepatic bile acid concentration was decreased in LKO mice only. In contrast, biliary phospholipid level was decreased only in TKO mice, while biliary cholesterol levels were unaltered regardless of phenotype. The loss of either or both genes increased hepatic expression of the major bile acid synthetic enzymes (CYP7A1 and/or CYP27A1). Loss of L-FABP and/or SCP-2/SCP-x genes significantly altered the molecular composition of biliary bile acids, but not the proportion of conjugated/unconjugated bile acids or overall bile acid hydrophobicity index. These data suggested that L-FABP was more important in hepatic retention of bile acids, while SCP-2/SCP-x more broadly affected biliary bile acid and phospholipid levels.
    Full-text · Article · Nov 2015 · Archives of Biochemistry and Biophysics
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    • "In this regard, it has also been shown that FABP1 can bind glucose and glucose-1-phosphate resulting in altered FABP1 conformation and increased affinity, uptake and distribution of lipidic ligands [10]. FABP1 function is also relevant for body weight and, depending on the diet type and the mouse strain, weight gain [11] [12] [13] [14] or protection against obesity [8] [15] [16] has been observed in FABP1 deficient mice. "
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    ABSTRACT: Liver fatty acid binding protein (FABP1) prevents lipotoxicity of free fatty acids and regulates fatty acid trafficking and partition. Our objective is to investigate the transcription factors controlling the human FABP1 gene and their regulation in nonalcoholic fatty liver disease (NAFLD). Adenovirus-mediated expression of multiple transcription factors in HepG2 cells and cultured human hepatocytes demonstrated that FOXA1 and PPARα are among the most effective activators of human FABP1, whereas C/EBPα is a major dominant repressor. Moreover, FOXA1 and PPARα induced re-distribution of FABP1 protein and increased cytoplasmic expression. Reporter assays demonstrated that the major basal activity of the human FABP1 promoter locates between -96 and -229bp, where C/EBPα binds to a composite DR1-C/EBP element. Mutation of this element at -123bp diminished basal reporter activity, abolished repression by C/EBPα and reduced transactivation by HNF4α. Moreover, HNF4α gene silencing by shRNA in HepG2 cells caused a significant down-regulation of FABP1 mRNA expression. FOXA1 activated the FABP1 promoter through binding to a cluster of elements between -229 and -592bp, whereas PPARα operated through a conserved proximal element at -59bp. Finally, FABP1, FOXA1 and PPARα were concomitantly repressed in animal models of NAFLD and in human nonalcoholic fatty livers, whereas C/EBPα was induced or did not change. We conclude that human FABP1 has a complex mechanism of regulation where C/EBPα displaces HNF4α and hampers activation by FOXA1 and PPARα. Alteration of expression of these transcription factors in NAFLD leads to FABP1 gen repression and could exacerbate lipotoxicity and disease progression.
    Full-text · Article · Jan 2013 · Biochimica et Biophysica Acta
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    • "Thus, effects of genetic polymorphisms may be more articulated in females through such transcriptional upregulation. This also explains the absence of the interaction between gender and FABP2 (intestinal type), whereas sex-dimorphic effects of FABP1 (liver-type) knockout have been noted in rodent models [54, 55]. "
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    ABSTRACT: Dysfunctional lipid metabolism plays a central role in pathogenesis of major chronic diseases, and genetic factors are important determinants of individual lipid profiles. We analyzed the associations of two well-established functional polymorphisms (FABP2 A54T and APOE isoforms) with past and family histories of 1492 population samples. FABP2-T54 allele was associated with an increased risk of past history of myocardial infarction (odds ratio (OR) = 1.51). Likewise, the subjects with APOE4, compared with E2 and E3, had a significantly increased risk of past history myocardial infarction (OR = 1.89). The OR associated with APOE4 was specifically increased in women for past history of myocardial infarction but decreased for gallstone disease. Interactions between gender and APOE isoforms were also significant or marginally significant for these two conditions. FABP2-T54 allele may be a potential genetic marker for myocardial infarction, and APOE4 may exert sex-dependent effects on myocardial infarction and gallbladder disease.
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