Targeted Deletion of FATP5 Reveals Multiple Functions in Liver Metabolism: Alterations in Hepatic Lipid Homeostasis

Stanford University, Palo Alto, California, United States
Gastroenterology (Impact Factor: 16.72). 05/2006; 130(4):1245-58. DOI: 10.1053/j.gastro.2006.02.006
Source: PubMed


Fatty acid transport protein 5 (FATP5/Slc27a5) has been shown to be a multifunctional protein that in vitro increases both uptake of fluorescently labeled long-chain fatty acid (LCFA) analogues and bile acid/coenzyme A ligase activity on overexpression. The aim of this study was to further investigate the diverse roles of FATP5 in vivo.
We studied FATP5 expression and localization in liver of C57BL/6 mice in detail. Furthermore, we created a FATP5 knockout mouse model and characterized changes in hepatic lipid metabolism (this report) and bile metabolism (the accompanying report by Hubbard et al).
FATP5 is exclusively expressed by the liver and localized to the basal plasma membrane of hepatocytes, congruent with a role in LCFA uptake from the circulation. Overexpression of FATP5 in mammalian cells increased the uptake of 14C-oleate. Conversely, FATP5 deletion significantly reduced LCFA uptake by hepatocytes isolated from FATP5 knockout animals. Moreover, FATP5 deletion resulted in lower hepatic triglyceride and free fatty acid content despite increased expression of fatty acid synthetase and also caused a redistribution of lipids from liver to other LCFA-metabolizing tissues. Detailed analysis of the hepatic lipom of FATP5 knockout livers showed quantitative and qualitative alterations in line with a decreased uptake of dietary LCFAs and increased de novo synthesis.
Our findings support the hypothesis that efficient hepatocellular uptake of LCFAs, and thus liver lipid homeostasis in general, is largely a protein-mediated process requiring FATP5. These new insights into the physiological role of FATP5 should lead to an improved understanding of liver function and disease.

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    • "These mice also fail to gain weight on a HFD because of both decreased food intake and increased energy expenditure [101]. Excitingly, induced knockdown of Fatp5 in the liver can reverse already established diet-induced hepatic steatosis in mice [100]. Thus, in mammals FATP1 and FATP5 promote TAG storage by increasing FA uptake and therefore are promising therapeutic candidates for obesity, diabetes and non-alcoholic fatty liver disease. "
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    ABSTRACT: The dysregulation of lipid metabolism has been implicated in various diseases, including diabetes, cardiopathies, dermopathies, retinal and neurodegenerative diseases. Mouse models have provided insights into lipid metabolism. However, progress in the understanding of these pathologies is hampered by the multiplicity of essential cellular processes and genes that modulate lipid metabolism. Drosophila and C. elegans have emerged as simple genetic models to improve our understanding of these metabolic diseases. Recent studies have characterized fatty acid transport protein (fatp) mutants in Drosophila and C. elegans, establishing new models of cardiomyopathy, retinal degeneration, fat storage disease and dermopathies. These models have generated novel insights into the physiological role of the Fatp protein family in vivo in multicellular organisms, and are likely to contribute substantially to progress in understanding the etiology of various metabolic disorders. Here, we describe and discuss the mechanisms underlying invertebrate fatp mutant models in the light of the current knowledge relating to FATPs and lipid disorders in vertebrates.
    Progress in lipid research 09/2015; 60. DOI:10.1016/j.plipres.2015.08.001 · 10.02 Impact Factor
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    • "Briefly, LCFAs interact with membrane FATPs to be transported from the exoplasmic side to the cytoplasmic side of the cell membrane. The crucial mechanistic importance of FATPs for LCFAs internalization, form blood into organs and tissues, was confirmed through the use of FATP5 [25] and FATP1 [26] knockout (KO) mice models. Since FATP transport is Table 3 Fatty acid concentrations in the liver of APOE-targeted replacement mice carrying human APOE isoforms or of Wild-type C57/BL6 mice a . "
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    ABSTRACT: Evidences suggest that omega-3 fatty acid (n-3 PUFA) metabolism is imbalanced in apolipoprotein E epsilon 4 isoform carriers (APOE4). This study aimed to investigate APOE genotype-dependant modulation of FA profiles, protein and enzyme important to fatty acid (FA) metabolism in the adipose tissue, the liver and the plasma using human APOE-targeted replacement mouse-model (N=37). FA transport (FATP) and binding (FABP) protein levels in tissues and concentrations of liver carnitine palmitoyltransferase 1 (CPT1) were performed. N-3 PUFA concentration was >45% lower in the adipose tissue and liver of APOE4 mice compared to APOE3 mice. In APOE4 mice, there were higher levels of FATP and FABP in the liver and higher FATP in the adipose tissue compared to APOE2 mice. There was a trend towards higher CPT1 concentrations in APOE4 mice compared to APOE3 mice. Therefore, since APOE-isoform differences were not always in line with the unbalanced n-3 PUFA profiles in organs, other proteins may be involved in maintaining n-3 PUFA homeostasis in mice with different APOE-isoforms.
    Prostaglandins Leukotrienes and Essential Fatty Acids 09/2014; 91(6). DOI:10.1016/j.plefa.2014.09.007 · 2.35 Impact Factor
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    • "Whether increased hepatic Fatp5 activity upon over expression of 11β-HSD1 contributes to steatosis is currently unknown and this deserves further investigation. Fatp5 plays an essential role in fatty acid partitioning among metabolic active organs [38], and Fatp5-deficient mice display a redistribution of lipids from the liver to other tissues. Fatp5 has been proposed as a potential target for treatment of non-alcoholic fatty liver disease [37,58]. "
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    ABSTRACT: 11β-Hydroxysteroid dehydrogenase-1 (11β-HSD1) plays a key role in glucocorticoid receptor (GR) activation. Besides, it metabolizes some oxysterols and bile acids (BAs). The GR regulates BA homeostasis; however, the impact of impaired 11β-HSD1 activity remained unknown. We profiled plasma and liver BAs in liver-specific and global 11β-HSD1-deficient mice. 11β-HSD1-deficiency resulted in elevated circulating unconjugated BAs, an effect more pronounced in global than liver-specific knockout mice. Gene expression analyses revealed decreased expression of the BA-CoA ligase Fatp5, suggesting impaired BA amidation. Reduced organic anion-transporting polypeptide-1A1 (Oatp1a1) and enhanced organic solute-transporter-β (Ostb) mRNA expression were observed in livers from global 11β-HSD1-deficient mice. The impact of 11β-HSD1-deficiency on BA homeostasis seems to be GR-independent because intrahepatic corticosterone and GR target gene expression were not substantially decreased in livers from global knockout mice. Moreover, Fatp5 expression in livers from hepatocyte-specific GR knockout mice was unchanged. The results revealed a role for 11β-HSD1 in BA homeostasis.
    Molecular Metabolism 08/2014; 3(5). DOI:10.1016/j.molmet.2014.04.008
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