Variants in the PPARγ gene affect fatty acid and glycerol metabolism in familial combined hyperlipidemia

Eurlings, Petra M.H.; Kallen, Carla; Vermeulen, Vicky M. M.-J.; Bruin, T.W.A. de

doi:10.1016/s1096-7192(03)00138-0

Cited by 10 publications

(4 citation statements)

References 33 publications

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“…24 -26 In 2 independent studies, PPAR-␥ SNPs were marginally associated with free fatty acid and glycerol levels as well as decreased fasting insulin levels in FCHL probands. 19,27 We identified 2 common PPAR-␥ haplotypes, 1 risk and 1 protective haplotype, which were associated with the desaturation index, suggesting that common variants of PPAR-␥ may contribute to variation in SCD1 activity, although the observed association was relatively weak. Replication of this finding is warranted.…”

Section: Discussionmentioning

confidence: 92%

“…Two of these regions, 3p26.1 to 3p13 and 20p11.21 to 20q13.32, are located near genes which have been previously associated with either free fatty acid or triglyceride levels in FCHL cohorts. 19,20 No evidence for linkage was obtained for the region containing the SCD1 gene on chromosome 10 ( Figure 1). Additional adjustment of the desaturation index for triglyceride and HDL-C levels did not significantly alter the results (Figure 1 The strongest evidence for linkage was located on chromosome 3 near the PPAR-␥ gene (zϭ2.7, Pϭ0.003).…”

Section: Resultsmentioning

confidence: 99%

“…Seven tagging SNPs and 2 coding SNPs (rs1801282, also known as the Pro12Ala polymorphism and rs3856806, also known as C161T), which had previously been studied in our case-control set, were genotyped in our FCHL families. 19 These 9 SNPs span a total of 141 kb. Pairwise linkage disequilibrium (LD) was similar Z scores and P values for age-and sex-adjusted and for age-, sex-, tg-, and hdlc-() adjusted desaturation index trait.…”

Section: Resultsmentioning

confidence: 99%

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Association of Stearoyl-CoA Desaturase 1 Activity With Familial Combined Hyperlipidemia

Mar‐Heyming

Miyazaki

Weissglas‐Volkov

et al. 2008

ATVB

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Objective-Stearoyl-CoA desaturase 1 (SCD1) is the rate-limiting enzyme involved in the synthesis of monounsaturated fatty acids, and in mice SCD1 activity is associated with plasma triglyceride levels. We used the fatty acid desaturation index (the plasma ratio of 18:1/18:0) as a marker of SCD1 activity to investigate the relationship of SCD1 to familial combined hyperlipidemia (FCHL). Methods and Results-The fatty acid desaturation index was measured in 400 individuals from 18 extended FCHL pedigrees. FCHL-affected individuals exhibited increased SCD1 activity when compared to unrelated controls (PϽ0.0001). The fatty acid desaturation index was found to be highly heritable (h 2 ϭ0.48, Pϭ2.2ϫ10 Ϫ11 ) in this study sample. QTL analysis in 346 sibling pairs from 18 FCHL families revealed suggestive linkage of the desaturation index to chromosomes 3p26.1 to 3p13 (zϭ2.7, Pϭ0.003), containing the peroxisome proliferator-activated receptor gamma (PPAR␥) gene, and 20p11.21 to 20q13.32 (zϭ1.7, Pϭ0.04), containing the hepatocyte nuclear factor 4, alpha (HNF4␣) gene. A specific haplotype of HNF4␣ was found to be associated with the desaturation index in these FCHL families (Pϭ0.002). Conclusion-Our results demonstrate that the fatty acid desaturation index is a highly heritable trait that is associated with the dyslipidemia observed in FCHL. (Arterioscler Thromb Vasc Biol 2008;28:1193-1199)Key Words: familial combined hyperlipidemia Ⅲ genetics Ⅲ Stearoyl-CoA desaturase 1 Ⅲ peroxisome proliferator-activated receptor gamma Ⅲ hepatocyte nuclear factor 4 alpha S tearoyl-coenzyme A (CoA) desaturase (SCD) is the major enzyme which catalyzes the conversion of saturated fatty acids to monounsaturated fatty acids. The primary products of SCD-1, palmitate and oleate, are the most abundant monounsaturated fatty acids of phospholipids, triglycerides, wax esters, and cholesterol esters. 1 Mice homozygous for either a naturally occurring mutation or a targeted disruption of the SCD1 gene exhibit a marked reduction in VLDL triglycerides. 2 SCD1 Ϫ/Ϫ mice on a leptin-deficient ob/ob background exhibit reduced adiposity and increased fatty acid oxidation when compared to control animals, demonstrating a key role for SCD1 in the regulation of lipid homeostasis. 2 Familial combined hyperlipidemia (FCHL) is characterized by elevated plasma triglyceride or cholesterol levels. 3 FCHL often occurs in combination with insulin resistance, central adiposity, altered fatty acid metabolism, and other dyslipidemic phenotypes that predispose to early coronary artery disease (CAD). 4,5 The observed role of SCD1 in the regulation of VLDL metabolism and its involvement in many of the lipid parameters that are perturbed in FCHL suggest that the activity of this enzyme may be altered in FCHL subjects. In fact, the desaturation index was strongly correlated with both triglyceride and HDL levels in a human cohort of which approximately 60% of the subjects had FCHL. 6 In mice, studies of SCD activity in the HYPLIP mouse model of hyperlipidemia showed that hepa...

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Section: Discussionmentioning

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Association of Stearoyl-CoA Desaturase 1 Activity With Familial Combined Hyperlipidemia

Mar‐Heyming

Miyazaki

Weissglas‐Volkov

et al. 2008

ATVB

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“…Several candidate genes have been evaluated for their contribution to the FCH phenotype. These include genes involved in lipid metabolism, such as lipoprotein lipase, hepatic lipase, ApoAI/ CIII/AIV, and apoAV [89][90][91][92][93][94][95][96][97][98][99][100] ; in adipose tissue metabolism, such as TNF 101 and HSL 70,71 ; and in insulin resistance and FFA metabolism (fatty acid binding protein, 102 insulin receptor substrate gene and b 3 -adrenergic receptor, 103 and PPAR-g 104,105 ). To summarize the results of these studies, LPL and ApoAI/CIII/AIV have been most consistently associated as modifier genes in FCH.…”

Section: Genetics Of Fchmentioning

confidence: 99%

Diagnostic Criteria in Relation to the Pathogenesis of Familial Combined Hyperlipidemia

J¹,

G²,

Af³

2004

Seminars in Vascular Medicine

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Familial combined hyperlipidemia (FCH) is the most common inherited hyperlipidemia in humans, affecting 1 to 3% of the adult population and up to 20% of patients with premature myocardial infarction. FCH is traditionally diagnosed by total plasma cholesterol and/or triglyceride levels above the 90th percentile adjusted for age and gender; however, the diagnosis of FCH based on these diagnostic criteria is inconsistent in 26% of the subjects over a five-year period, emphasizing the need for re-evaluation of the diagnostic criteria for FCH. Recently, a nomogram was developed based on absolute apolipoprotein B levels in combination with triglyceride and total cholesterol levels adjusted for both age and gender to simply and accurately diagnose FCH. When percentiles of triglyceride and total cholesterol adjusted for age and gender are not available in a population, the definition of FCH can be established based on hypertriglyceridemia (> 1.5 mmol/l) and hyperapoB (> 1200 mg/l). Standardized and simple diagnostic criteria are necessary to further delineate the pathogenesis of FCH. Several metabolic pathways have been suggested to be important in causing the FCH phenotype including hepatic VLDL overproduction either with or without impaired clearance of triglyceride-rich lipoproteins from plasma. The presence of insulin resistance and obesity in FCH patients further contribute to the expression of the lipidphenotype. A disturbed adipose tissue metabolism that results in an increased plasma free fatty acid pool may be the culprit in the pathogenesis of FCH.

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Radiological evidence of nonalcoholic fatty liver disease in familial combined hyperlipidemia

Bruin

Georgieva

Brouwers

et al. 2004

The American Journal of Medicine

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Variants in the PPARγ gene affect fatty acid and glycerol metabolism in familial combined hyperlipidemia

Cited by 10 publications

References 33 publications

Association of Stearoyl-CoA Desaturase 1 Activity With Familial Combined Hyperlipidemia

Association of Stearoyl-CoA Desaturase 1 Activity With Familial Combined Hyperlipidemia

Diagnostic Criteria in Relation to the Pathogenesis of Familial Combined Hyperlipidemia

Radiological evidence of nonalcoholic fatty liver disease in familial combined hyperlipidemia

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