GPR41 Gene Expression Is Mediated by Internal Ribosome Entry Site (IRES)-dependent Translation of Bicistronic mRNA Encoding GPR40 and GPR41 Proteins

Halpern, Keren Bahar; Veprik, Anna; Rubins, Nir; Naaman, Orly; Walker, Michael D.

doi:10.1074/jbc.m112.358887

Cited by 38 publications

(29 citation statements)

References 39 publications

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“…The simultaneous up-regulation of both FFAR1 and FFAR3 in response to oleate observed is in line with studies showing the existence of bicistronic mRNA encoding FFAR1 and FFAR3 [38]. Germane to the data presented here, FFAR3 ligands have also been indicated as potential positive regulators of L-cell mass [13].…”

Section: Discussionsupporting

confidence: 90%

Long chain saturated and unsaturated fatty acids exert opposing effects on viability and function of GLP-1-producing cells: Mechanisms of lipotoxicity

et al. 2017

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Background and aimFatty acids acutely stimulate GLP-1 secretion from L-cells in vivo. However, a high fat diet has been shown to reduce the density of L-cells in the mouse intestine and a positive correlation has been indicated between L-cell number and GLP-1 secretion. Thus, the mechanism of fatty acid-stimulated GLP-1 secretion, potential effects of long-term exposure to elevated levels of different fatty acid species, and underlying mechanisms are not fully understood. In the present study, we sought to determine how long-term exposure to saturated (16:0) and unsaturated (18:1) fatty acids, by direct effects on GLP-1-producing cells, alter function and viability, and the underlying mechanisms.MethodsGLP-1-secreting GLUTag cells were cultured in the presence/absence of saturated (16:0) and unsaturated (18:1) fatty acids (0.125 mM for 48 h, followed by analyses of viability and apoptosis, as well as involvement of fatty acid oxidation, free fatty acid receptors (FFAR1) and ceramide synthesis. In addition, effects on the expression of proglucagon, prohormone convertase 1/3 (PC1/3), free fatty acid receptors (FFAR1, FFAR3), sodium glucose co-transporter (SGLT) and subsequent secretory response were determined.ResultsSaturated (16:0) and unsaturated (18:1) fatty acids exerted opposing effects on the induction of apoptosis (1.4-fold increase in DNA fragmentation by palmitate and a 0.5-fold reduction by oleate; p<0.01). Palmitate-induced apoptosis was associated with increased ceramide content and co-incubation with Fumonisin B1 abolished this lipo apoptosis. Oleate, on the other hand, reduced ceramide content, and—unlike palmitate—upregulated FFAR1 and FFAR3, evoking a 2-fold increase in FFAR1-mediated GLP-1 secretion following acute exposure to 0.125 mmol/L palmitate; (p<0.05).Conclusion/InterpretationSaturated (16:0), but not unsaturated (18:1), fatty acids induce ceramide-mediated apoptosis of GLP-1-producing cells. Further, unsaturated fatty acids confer lipoprotection, enhancing viability and function of GLP-1-secreting cells. These data provide potential mechanistic insight contributing to reduced L-cell mass following a high fat diet and differential effects of saturated and unsaturated fatty acids on GLP-1 secretion in vivo.

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Section: Discussionsupporting

confidence: 90%

Long chain saturated and unsaturated fatty acids exert opposing effects on viability and function of GLP-1-producing cells: Mechanisms of lipotoxicity

et al. 2017

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“…GPR40 and GPR41 are encoded by a bicistronic transcript with GPR40 expression driven by a cap-dependent mechanism whereas GPR41 expression is regulated via an IRES [21]. GPR40, a medium and long-chain fatty acid receptor, causes increased Gαq/11-mediated intracellular calcium levels that stimulate the release of insulin in the presence of long-chain fatty acids [22].…”

Section: Why Polycistronic Genes?mentioning

confidence: 99%

“…Dysregulation of either or both of the cistrons may affect the pathology of metabolic disease. It has been hypothesized that co-expression of these fatty acid-activated receptors could sensitize beta cells to different types and levels of fatty acids [21]. …”

Section: Why Polycistronic Genes?mentioning

confidence: 99%

Mammalian Polycistronic mRNAs and Disease

et al. 2017

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Our understanding of gene expression has come far since the “one-gene one-polypeptide” hypothesis proposed by Beadle and Tatum. This review addresses the gradual recognition that a growing number of polycistronic genes, originally discovered in viruses, are being identified within the mammalian genome, and that these may provide new insights into disease mechanisms and treatment. We have carried out a systematic literature review identifying 13 mammalian genes for which there is evidence for polycistronic expression via translation through an Internal Ribosome Entry Site (IRES). Although the canonical mechanism of translation initiation has been studied extensively, this review highlights a process of non-canonical translation, IRES-mediated translation, that is a growing source of understanding complex inheritance, elucidation of disease mechanisms, and discovery of novel therapeutic targets. Identification of additional polycistronic genes may provide new insights into disease therapy and allow for new discoveries of translational and disease mechanisms.

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“…On the day of transfection, 200,000 cells/well in a 24-well plate coated with Matrigel were transfected with a mixture of 0.5 g of DNA (consisting of 100 ng of reporter construct, 50 ng of internal control, and 350 ng of pUC18) and 2 l of TransIT-2020 reagent in optimem medium (according to the manufacturer's protocol; Mirus). Cells were harvested 48 h after transfection, and cell extracts were subjected to protein concentration determination and luciferase reporter enzyme assays as described (19).…”

Section: Transient Transfectionsmentioning

confidence: 99%

Paradoxical Role of DNA Methylation in Activation of FoxA2 Gene Expression during Endoderm Development

Halpern

Vana

Walker

2014

Journal of Biological Chemistry

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GPR41 Gene Expression Is Mediated by Internal Ribosome Entry Site (IRES)-dependent Translation of Bicistronic mRNA Encoding GPR40 and GPR41 Proteins

Cited by 38 publications

References 39 publications

Long chain saturated and unsaturated fatty acids exert opposing effects on viability and function of GLP-1-producing cells: Mechanisms of lipotoxicity

Long chain saturated and unsaturated fatty acids exert opposing effects on viability and function of GLP-1-producing cells: Mechanisms of lipotoxicity

Mammalian Polycistronic mRNAs and Disease

Paradoxical Role of DNA Methylation in Activation of FoxA2 Gene Expression during Endoderm Development

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