Identification of Cd36 (Fat) as an insulin-resistance gene causing defective fatty acid and glucose metabolism in hypertensive rats

Aitman, Timothy J.; Glazier, Anne M.; Wallace, Caroline A.; Cooper, Lisa D.; Norsworthy, Penny J.; Wahid, Faisal; Al-Majali, Khulood M.; Trembling, Paul M.; Mann, Christopher; Shoulders, Carol C.; Graf, Daniel; Lezin, Elizabeth St.; Kurtz, Theodore W.; Křen, Vladimı́r; Pravenec, Michal; Ibrahimi, Azeddine; Abumrad, Nada A.; Stanton, Lawrence W.; Scott, James A.

doi:10.1038/5013

Cited by 679 publications

(496 citation statements)

References 48 publications

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“…Indeed, recent evidence demonstrates that the membrane protein CD36 (fatty acid translocase), which is a facilitator of long-chain fatty acids (Coburn et al, 2000), is deficient in a rat model of human metabolic syndrome X (Aitman et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Plasma AA and DHA levels are not compromised in newly diagnosed gestational diabetic women

et al. 2004

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Objective: The polyunsaturated fatty acids, arachidonic (AA) and docosahexaenoic (DHA), are vital structural and functional components of the neural, vascular and visual systems. There is increased demand for these fatty acids during pregnancy. Diabetes impairs the synthesis of both AA and DHA. We have investigated the possibility that pregnancy-induced diabetes compromises the levels of plasma AA and DHA in newly diagnosed expectant mothers. Design: Cross-sectional study. Setting: London, UK. Subjects and methods: Venous blood was obtained from 44 women with gestational diabetes mellitus (GDM) and from the same number of nondiabetics, during the third trimester. Fatty acid composition of plasma choline phosphoglycerides (CPG), triglycerides (TG) and cholesterol esters (CE) was analysed. Results: The GDM women had higher levels of AA (20:4n-6; Po0.0001) and AA/linoleic acid ratio (20:4n-6/18:2n-6; Po0.01) in the CPG, and linoleic acid (LA; Po0.0001), total n-6 (Po0.01), DHA (Po0.05) and n-3 metabolites (Po0.05) in TG compared to their nondiabetic counterparts. Similarly, AA (Po0.0001), osbond acid (22:5n-6; Po0.05), total n-6 metabolites (Po0.0001), AA/LA (Po0.0001) and n-6 metabolites/LA (Po0.01) were higher in the CE of the GDM women. There was no difference in the levels of DHA in CPG and CE between the two groups (P40.05). Conclusions:The results of this study do not provide evidence that the activity of delta-6 or delta-5 desaturases, which are vital for the synthesis of AA and DHA, is compromised by pregnancy-induced diabetes. However, since the samples were taken at diagnosis, it is conceivable that the duration of the diabetes was too short to have a discernable adverse effect on the levels of AA and DHA in plasma lipids.

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Section: Discussionmentioning

confidence: 99%

Plasma AA and DHA levels are not compromised in newly diagnosed gestational diabetic women

et al. 2004

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“…However, no apparent suitable candidate genes were initially discovered near the Lod score peak area. In the attempt to identify the gene(s) responsible for stroke phenotype within STR1, we performed, based on previous literature,7 a microarray differential expression analysis of all sequences contained inside STR1 in brains of both SHRSP and SHRSR fed with either regular or stroke permissive diet. One gene was found to be differentially modulated (ie, down‐regulated) in brains of SHRSP.…”

Section: Introductionmentioning

confidence: 99%

Ndufc2 Gene Inhibition Is Associated With Mitochondrial Dysfunction and Increased Stroke Susceptibility in an Animal Model of Complex Human Disease

Rubattu

Castro

Schulz

et al. 2016

JAHA

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BackgroundThe genetic basis of stroke susceptibility remains to be elucidated. STR1 quantitative trait locus (STR1/QTL) was identified on rat chromosome 1 of stroke‐prone spontaneously hypertensive rat (SHRSP) upon Japanese‐style stroke‐permissive diet (JD), and it contributes to 20% of the stroke phenotype variance.Methods and ResultsNine hundred eighty‐six probe sets mapping on STR1 were selected from the Rat RAE230A array and screened through a microarray differential expression analysis in brains of SHRSP and stroke‐resistant SHR (SHRSR) fed with either regular diet or JD. The gene encoding Ndufc2 (NADH dehydrogenase [ubiquinone] 1 subunit), mapping 8 Mb apart from STR1/QTL Lod score peak, was found significantly down‐regulated under JD in SHRSP compared to SHRSR. Ndufc2 disruption altered complex I assembly and activity, reduced mitochondrial membrane potential and ATP levels, and increased reactive oxygen species production and inflammation both in vitro and in vivo. SHRSR carrying heterozygous Ndufc2 deletion showed renal abnormalities and stroke occurrence under JD, similarly to SHRSP. In humans, T allele variant at NDUFC2/rs11237379 was associated with significant reduction in gene expression and with increased occurrence of early‐onset ischemic stroke by recessive mode of transmission (odds ratio [OR], 1.39; CI, 1.07–1.80; P=0.012). Subjects carrying TT/rs11237379 and A allele variant at NDUFC2/rs641836 had further increased risk of stroke (OR=1.56; CI, 1.14–2.13; P=0.006).ConclusionsA significant reduction of Ndufc2 expression causes complex I dysfunction and contributes to stroke susceptibility in SHRSP. Moreover, our current evidence may suggest that Ndufc2 can contribute to an increased occurrence of early‐onset ischemic stroke in humans.

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“…Insulin resistance is apparent in a genetic model of hypertension, the spontaneously hypertensive rat (SHR) [3,4], reinforcing the primary nature of the link between car-diovascular disorders and insulin resistance. Adipocytes derived from SHR rats exhibit attenuated insulin-stimulated glucose uptake and defective insulin-mediated inhibition of lipolysis compared with control normotensive rats [3,4]. We have recently extended these observations in a close relative of the SHR, the stroke-prone spontaneously hypertensive rat (SHRSP).…”

Section: Introductionmentioning

confidence: 99%

Reduced insulin-stimulated GLUT4 bioavailability in stroke-prone spontaneously hypertensive rats

et al. 2005

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Aims/hypothesis: Insulin-stimulated glucose transport is impaired in a genetic model of hypertension, the stroke-prone spontaneously hypertensive rat (SHRSP), yet the molecular mechanisms that underlie this defect in the animals remain unclear. Methods: We examined the effects of insulin on the trafficking of the insulin-responsive glucose transporter GLUT4 to the plasma membrane in isolated adipocytes from SHRSP and normotensive control WistarKyoto (WKY) rats. Results: Treatment of isolated adipocytes with insulin resulted in trafficking of GLUT4 to the plasma membrane. There was no significant difference in the magnitude of insulin-stimulated GLUT4 trafficking from intracellular membranes to the plasma membrane between strains. In contrast, we demonstrated that there is a significant reduction in GLUT4 accessible to the glucose photolabel Bio-LC-ATB-BGPA at the plasma membrane of SHRSP adipocytes compared with control rats. Conclusions/ interpretation: We propose that a large proportion of GLUT4 translocated to the plasma membrane in response to insulin is not able to bind substrate and catalyse transport in the SHRSP. Therefore, there is a reduction in bioavailable GLUT4 in SHRSP animals that is likely to account, at least in part, for the reduced insulin-stimulated glucose uptake.

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Identification of Cd36 (Fat) as an insulin-resistance gene causing defective fatty acid and glucose metabolism in hypertensive rats

Cited by 679 publications

References 48 publications

Plasma AA and DHA levels are not compromised in newly diagnosed gestational diabetic women

Plasma AA and DHA levels are not compromised in newly diagnosed gestational diabetic women

Ndufc2 Gene Inhibition Is Associated With Mitochondrial Dysfunction and Increased Stroke Susceptibility in an Animal Model of Complex Human Disease

Reduced insulin-stimulated GLUT4 bioavailability in stroke-prone spontaneously hypertensive rats

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