Influence of Peroxisome Proliferator-activated Receptor α Agonists on the Intracellular Turnover and Secretion of Apolipoprotein (Apo) B-100 and ApoB-48

Lindén, Daniel; Lindberg, Karin; Oscarsson, Jan; Claesson, Catharina; Asp, Lennart; Lu, Li; Gustafsson, Maria; Borén, Jan; Olofsson, Sven-Olof

doi:10.1074/jbc.m110416200

Cited by 85 publications

(79 citation statements)

References 52 publications

(78 reference statements)

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“…In fact, fenofibrate enters the liver cells with the help of transporters such as LFABP and is transferred to PPARa. The PPARa then binds to its response element in the target gene and increases the transcriptional rate of genes such as LFABP (Issemann et al 1992;Linden et al 2002;Schoonjans et al 1997). Unfortunately, no interaction between LFABP T94A and PPARa L162V genotypes were found to affect plasma lipid levels.…”

Section: Discussionmentioning

confidence: 99%

Effect of liver fatty acid binding protein (FABP) T94A missense mutation on plasma lipoprotein responsiveness to treatment with fenofibrate

et al. 2004

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Fenofibrate, a peroxisome proliferated activated receptor alpha (PPARa) agonist, has been shown to decrease plasma triglyceride (TG) and increase plasma highdensity lipoprotein (HDL) cholesterol levels despite a large interindividual variation in the response. Fenofibrate-activated PPARa binds to a DNA sequence element termed PPAR response element (PPRE) present in regulatory regions of target genes. A PPRE has been identified in the proximal 5¢ flanking region of the gene encoding the liver fatty acid binding protein (LFABP). LFABP is a small cytosolic protein of 14 kDa present in the liver and the intestine and is a member of the superfamily of the fatty acid binding proteins (FABPs). FABPs play a role in the solubilization of long-chain fatty acids (LCFAs) and their CoA-ester to various intracellular organelles. FABPs serves as intracellular acceptors of LCFAs, and they may also have an impact in ligand-dependent transactivation of PPARs in trafficking LCFAs to the nucleus. Since PPARs are known to regulate the transcription of many genes involved in lipid metabolism, the importance of LFABP in fatty acid uptake has to be considered. The aim of this study was to verify whether genetic variations in the LFABP gene may impact on plasma lipoprotein/lipid levels in the fasting state as well as on the response to a lipid-lowering therapy with fenofibrate on plasma lipids and obesity variables. We also wanted to verify whether the presence of the PPARa L162V mutation interacts with genetic variants in LFABP gene. To achieve this goal, we first determined the genomic structure of the human LFABP gene and then designed intronic primers to sequence the coding regions, all exon-intron splicing boundaries, and the promoter region of the gene in 24 patients showing divergent plasma lipoprotein/lipid response to fenofibrate. Sequence analysis revealed the presence of a T94A missense mutation in exon 3. Interspecies comparison revealed that threonine 94 is conserved among species. We subsequently screened another sample of 130 French Canadian subjects treated with fenofibrate for the presence of the LFABP T94A mutation. Carriers of the A94 allele were at increased risk to exhibit plasma TG levels above 2.00 mmol/l after treatment with fenofibrate [2.75 (1.03-7.34); OR 95% confidence interval (CI)]. In addition, carriers of the A94 allele were characterized by higher baseline plasma-free fatty acid levels (FFA) (p=0.01) and by a lower body mass index (BMI) (p=0.05) and waist circumference (p=0.005) than T94 homozygotes. Moreover, PPARa L162V and LFABP T94A showed to have a synergistic effect on BMI (p interaction = 0.03). These results suggest that the LFABP T94A missense mutation could influence obesity indices as well as the risk to exhibit residual hypertriglyceridmia following a lipid-lowering therapy with fenofibrate.

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Section: Discussionmentioning

confidence: 99%

Effect of liver fatty acid binding protein (FABP) T94A missense mutation on plasma lipoprotein responsiveness to treatment with fenofibrate

et al. 2004

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“…Interestingly in primary hepatocytes PPAR α agonist (WY 14643) decreased the synthesis and secretion of triglycerides in the face of increased synthesis of apo B 100 [175]. The end re-sult was the formation of more apo B 100 containing particles with fewer triglycerides, i.e.…”

Section: New Perspectives Of Lipid Management In Type 2 Diabetesmentioning

confidence: 99%

Diabetic dyslipidaemia: from basic research to clinical practice*

2003

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The recognition that the increase of plasma triglyceride rich lipoproteins (TRLs) is associated with multiple alterations of other lipoproteins species that are potentially atherogenic has expanded the picture of diabetic dyslipidaemia. The discovery of heterogeneity within major lipoprotein classes VLDL, LDL and HDL opened new avenues to reveal the specific pertubations of diabetic dyslipidaemia. The increase of large VLDL 1 particles in Type 2 diabetes initiates a sequence of events that generates atherogenic remnants, small dense LDL and small dense HDL particles. Together these components comprise the atherogenic lipid triad. Notably the malignant nature of diabetic dyslipidaemia is not completely shown by the lipid measures used in clinical practice. The key question is what are the mechanisms behind the increase of VLDL 1 particles in diabetic dyslipidaemia? Despite the advances of recent years, our understanding of VLDL assembly and secretion is still surprisingly incomplete. To date it is still unclear how the liver is able to regulate the amount of triglycerides incorporated into VLDL particles to produce either VLDL 1 or VLDL 2 particles. The current evidence suggests that the machinery driving VLDL assembly in the liver includes (i) low insulin signalling via PI-3 kinase pathway that enhances lipid accumulation into "nascent" VLDL particles (ii) up-regulation of SREBP-1C that stimulates de novo lipogenesis and (iii) excess availability of "polar molecules" in hepatocytes that stabilizes apo B 100. Recent data suggest that all these steps could be fundamentally altered in Type 2 diabetes explaining the overproduction of VLDL apo B as well as the ability of insulin to suppress VLDL 1 apo B production in Type 2 diabetes.Recent discoveries have established the transcription factors including PPARs, SREBP-1 and LXRs as the key regulators of lipid assembly in the liver. These observations suggest these factors as a new target to tailor more efficient drugs to treat diabetic dyslipidaemia. [Diabetologia (2003) 46:733-749]

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“…HepG2 hepatoma cells expressing an L-FABP antisense RNA showed a dose-dependent reduction of fatty acid uptake (10). Furthermore, overexpression of L-FABP in McA-RH7777 hepatoma cells incubated with palmitic acid decreased the synthesis and secretion of triglycerides while increasing beta oxidation and the secretion of apolipoprotein B100 (11). Thus, the various in vitro systems have allowed researchers to propose specific functions of L-FABP in vivo.…”

mentioning

confidence: 99%

Decreased Liver Fatty Acid Binding Capacity and Altered Liver Lipid Distribution in Mice Lacking the Liver Fatty Acid-binding Protein Gene

Martin

Danneberg

Kumar

et al. 2003

Journal of Biological Chemistry

156

183

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Although liver fatty acid-binding protein (L-FABP) isan important binding site for various hydrophobic ligands in hepatocytes, its in vivo significance is not understood. We have therefore created L-FABP null mice and report here their initial analysis, focusing on the impact of this mutation on hepatic fatty acid binding capacity, lipid composition, and expression of other lipid-binding proteins. Gel-filtered cytosol from L-FABP null liver lacked the main fatty acid binding peak in the fraction that normally comprises both L-FABP and sterol carrier protein-2 (SCP-2). The binding capacity for cis-parinaric acid was decreased >80% in this region. Molar ratios of cholesterol/cholesterol ester, cholesteryl ester/triglyceride, and cholesterol/phospholipid were 2-to 3-fold greater, reflecting up to 3-fold absolute increases in specific lipid classes in the order cholesterol > cholesterol esters > phospholipids. In contrast, the liver pool sizes of nonesterified fatty acids and triglycerides were not altered. However, hepatic deposition of a bolus of intravenously injected family (1-3), is found in the liver, intestine, and kidney, but only in liver is it not co-expressed with other members of its family. L-FABP is known to bind fatty acids and various other hydrophobic molecules, although its actual contribution to the lipid-binding capacity of liver cytosol is not known. Given that L-FABP is expressed at very high levels (2-5% of cytosolic protein) in the differentiated hepatocyte (4, 5) and that these levels correlate well with lipid metabolism (2), it can be speculated that L-FABP contributes considerably to hepatic lipidbinding and lipid metabolism. Work with cell-free systems and transfected cells has further strengthened this view. For example, in cell-free preparations L-FABP was shown to stimulate the esterification of oleic acid while inhibiting that of palmitic acid (6). L cells overexpressing L-FABP show increased rates of fatty acid uptake and esterification (7) as well as increased contents of phospholipid and cholesterol esters (8, 9). HepG2 hepatoma cells expressing an L-FABP antisense RNA showed a dose-dependent reduction of fatty acid uptake (10). Furthermore, overexpression of L-FABP in McA-RH7777 hepatoma cells incubated with palmitic acid decreased the synthesis and secretion of triglycerides while increasing beta oxidation and the secretion of apolipoprotein B100 (11). Thus, the various in vitro systems have allowed researchers to propose specific functions of L-FABP in vivo.However, in vitro studies of FABPs have inherent limitations. The only firmly established function of FABPs is the reversible binding of hydrophobic ligands, and these proteins do not exhibit any enzymatic function or energy requirement. This suggests that these proteins play passive (facilitative) roles that, almost by definition, are strongly dependent on the cellular context. One context of the highly expressed L-FABP is the highly differentiated hepatocyte, a cell type featuring an intense lipid metabolism that is not eas...

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Influence of Peroxisome Proliferator-activated Receptor α Agonists on the Intracellular Turnover and Secretion of Apolipoprotein (Apo) B-100 and ApoB-48

Cited by 85 publications

References 52 publications

Effect of liver fatty acid binding protein (FABP) T94A missense mutation on plasma lipoprotein responsiveness to treatment with fenofibrate

Effect of liver fatty acid binding protein (FABP) T94A missense mutation on plasma lipoprotein responsiveness to treatment with fenofibrate

Diabetic dyslipidaemia: from basic research to clinical practice*

Decreased Liver Fatty Acid Binding Capacity and Altered Liver Lipid Distribution in Mice Lacking the Liver Fatty Acid-binding Protein Gene

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