A missense mutation in hepatocyte nuclear factor-4 alpha, resulting in a reduced transactivation activity, in human late-onset non-insulin-dependent diabetes mellitus.

Hani, El Habib; Suaud, Laurence; Boutin, Philippe; Chèvre, Jean-Claude; Durand, Emmanuelle; Philippi, Anne; Demenais, Florence; Vionnet, Nathalie; Furuta, Hiroto; Velho, Gilberto; Bell, Graeme I.; Lainé, Bernard; Froguel, Philippe

doi:10.1172/jci1403

Cited by 114 publications

(82 citation statements)

References 36 publications

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“…Moreover, the two crucial regulatory TFs regulating hepatic lipogenesis, Srebp1 and Chrebp1, are also targets of Hnf4a, demonstrated by other groups and this study, respectively (22). Reduced levels of Hnf4a have been implicated in the pathogenesis of type 2 diabetes mellitus and type 1 form of maturity-onset diabetes of the young (13,(23)(24)(25)(26). The large number of hepatic genes affected by the misregulation of Hnf4a is thought to cause the impaired insulin signaling in these metabolic syndromes (20).…”

Section: Discussionmentioning

confidence: 57%

Adiponectin regulates expression of hepatic genes critical for glucose and lipid metabolism

Liu

Yuan

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

126

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The effects of adiponectin on hepatic glucose and lipid metabolism at transcriptional level are largely unknown. We profiled hepatic gene expression in adiponectin knockout (KO) and wild-type (WT) mice by RNA sequencing. Compared with WT mice, adiponectin KO mice fed a chow diet exhibited decreased mRNA expression of ratelimiting enzymes in several important glucose and lipid metabolic pathways, including glycolysis, tricarboxylic acid cycle, fatty-acid activation and synthesis, triglyceride synthesis, and cholesterol synthesis. In addition, binding of the transcription factor Hnf4a to DNAs encoding several key metabolic enzymes was reduced in KO mice, suggesting that adiponectin might regulate hepatic gene expression via Hnf4a. Phenotypically, adiponectin KO mice possessed smaller epididymal fat pads and showed reduced body weight compared with WT mice. When fed a high-fat diet, adiponectin KO mice showed significantly reduced lipid accumulation in the liver. These lipogenic defects are consistent with the down-regulation of lipogenic genes in the KO mice.hepatic metabolism | lipogenesis | transcriptional regulation A dipose tissue regulates energy homeostasis by secreting cytokines known as adipokines. Adiponectin, the most abundant adipokine in the serum, modulates lipid and glucose metabolism, including promotion of fatty acid oxidation and glucose utilization and repression of hepatic gluconeogenesis (1, 2). Several lines of adiponectin knockout (KO) or transgenic (Tg) mice have been generated in different laboratories (3, 4). Although the phenotypes reported are variable in some aspects, these mouse models all demonstrate that adiponectin deficiency predisposed mice to high-fat-diet (HFD)-induced insulin resistance (3-5). It was proposed that adiponectin is required to maintain a basal tone of insulin responsiveness (5). However, the way in which the basal tone of insulin responsiveness is established and how adiponectin maintains insulin sensitivity remain largely unknown.Adiponectin is present in plasma at extremely high concentrations (2-10 μg/mL), in contrast to that of insulin, glucagon, and leptin, which are found at orders-of-magnitude smaller concentrations. Moreover, most metabolic hormones are released into the blood in a regulated pulsatile fashion (6); this process allows the insulin's actions to respond to nutritional signals following meals or for glucagon to increase hepatic glucose output during hypoglycemia. In contrast, the blood levels of adiponectin are strikingly constant, making adiponectin a less-sensitive regulator in response to the acute changes in glucose and lipid levels following food intake or deprivation. We therefore hypothesize that adiponectin primarily regulates glucose and lipid metabolism at transcriptional levels besides its well described role that involves AMP-activated protein kinase (AMPK).To test this hypothesis, we profiled hepatic gene expression in both wild-type (WT) and adiponectin KO mice fed a standard chow diet by high-throughput RNA sequencing (RNA-Seq). ...

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Section: Discussionmentioning

confidence: 57%

Adiponectin regulates expression of hepatic genes critical for glucose and lipid metabolism

Liu

Yuan

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

126

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“…In contrast, the widespread polymorphism (Pro12Ala allele) is protective against T2D in Caucasians, but not in South Asians [9,27]. Similarly, different mutations in HNF4A or IPF1 can lead to either pancreatic agenesis (for homozygous dominant-negative frameshift mutation in IPF1), MODY (for heterozygous dominant-negative frameshift mutation in IPF1, or loss of function mutation in HNF4A), or late-onset diabetes (for missense mutations in IPF1 or HNF4A) [28][29][30]. Studies examining prediabetic glycemic traits (fasting insulin, fasting glucose, glucose, and insulin levels after glucose challenge) have identified that loci implicated in T2D susceptibility can also harbor variants that correlate with continuous glycemic traits.…”

Section: Finding the Genetic Determinants Of Common Type 2 Diabetes -mentioning

confidence: 99%

Genetic and environmental factors associated with type 2 diabetes and diabetic vascular complications

Murea

Ma²,

Freedman³

2012

Rev Diabet Stud

298

188

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Faced with a global epidemic of type 2 diabetes (T2D), it is critical that researchers improve our understanding of the pathogenesis of T2D and related vascular complications. These findings may ultimately lead to novel treatment options for disease prevention or delaying progression. Two major paradigms jointly underlie the development of T2D and related coronary artery disease, diabetic nephropathy, and diabetic retinopathy. These paradigms include the genetic risk variants and behavioral/environmental factors. This article systematically reviews the literature supporting genetic determinants in the pathogenesis of T2D and diabetic vasculopathy, and the functional implications of these gene variants on the regulation of beta-cell function and glucose homeostasis. We update the discovery of diabetes and diabetic vasculopathy risk variants, and describe the genetic technologies that have uncovered them. Also, genomic linkage between obesity and T2D is discussed. There is a complementary role for behavioral and environmental factors modulating the genetic susceptibility and diabetes risk. Epidemiological and clinical data demonstrating the effects of behavioral and novel environmental exposures on disease expression are reviewed. Finally, a succinct overview of recent landmark clinical trials addressing glycemic control and its impact on rates of vascular complications is presented. It is expected that novel strategies to exploit the gene-and exposure-related underpinnings of T2D will soon result.

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“…This region includes a major positional candidate, the transcription factor hepatocyte nuclear factor (HNF)-4α gene whose coding mutations cause MODY1 [4] and more rarely familial monogenic late-onset type 2 diabetes [5]. In both cases, defective insulin secretion was shown in diabetic and not yet diabetic mutation carriers.…”

Section: Introductionmentioning

confidence: 99%

Effect of common polymorphisms in the HNF4? promoter on susceptibility to type 2 diabetes in the French Caucasian population

et al. 2005

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Aims/hypothesis: The gene encoding HNF-4α, an orphan nuclear receptor playing critical roles in embryogenesis and metabolism by regulating gene expression in pancreatic beta cells, liver, and other tissues, is localised to chromosome 20q13, where linkage to type 2 diabetes has been shown in multiple studies. As two reports have independently demonstrated a convincing association with variants adjacent to the HNF-4α P2 promoter in Finnish and Ashkenazi Jewish populations, we evaluated their contribution to diabetes risk in the French Caucasian population. Methods: Genotypes for four haplotype tag SNPs were analysed for association with diabetes in a casecontrol study of 744 unrelated type 2 diabetic patients and 686 normoglycaemic subjects, and for linkage in 148 diabetic families in whom significant linkage to the HNF4α region had been shown. Results: The association seen in the Finnish and Ashkenazi studies for SNPs rs2144908 and rs1884614 located within a haplotype block encompassing the beta cell promoter P2 of HNF-4α was not replicated in our study; in French Caucasians the minor allele prevalence was increased in control subjects [odds ratio (OR) 0.80, uncorrected p=0.022 for rs2144908; OR 0.82 uncorrected p=0.058 for rs1884614]. Furthermore, none of the SNPs tested in the French familial sample was associated with diabetes, nor do they appear to contribute to the linkage. Conclusions/interpretation: None of the previously associated SNPs confer an increased risk for diabetes in French Caucasians. A large meta-analysis of association studies will determine whether there is a consistent association between particular SNPs upstream of HNF-4α and type 2 diabetes in several ethnic groups.

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A missense mutation in hepatocyte nuclear factor-4 alpha, resulting in a reduced transactivation activity, in human late-onset non-insulin-dependent diabetes mellitus.

Cited by 114 publications

References 36 publications

Adiponectin regulates expression of hepatic genes critical for glucose and lipid metabolism

Adiponectin regulates expression of hepatic genes critical for glucose and lipid metabolism

Genetic and environmental factors associated with type 2 diabetes and diabetic vascular complications

Effect of common polymorphisms in the HNF4? promoter on susceptibility to type 2 diabetes in the French Caucasian population

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