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CD36-dependent regulation of muscle FoxO1 and PDK4 in the PPAR delta/beta-mediated adaptation to metabolic stress.

ABSTRACT: The transcription factor FoxO1 contributes to the metabolic adaptation to fasting by suppressing muscle oxidation of glucose, sparing it for glucose-dependent tissues. Previously, we reported that FoxO1 activation in C(2)C(12) muscle cells recruits the fatty acid translocase CD36 to the plasma membrane and increases fatty acid uptake and oxidation. This, together with FoxO1 induction of lipoprotein lipase, would promote the reliance on fatty acid utilization characteristic of the fasted muscle. Here, we show that CD36-mediated fatty acid uptake, in turn, up-regulates protein levels and activity of FoxO1 as well as its target PDK4, the negative regulator of glucose oxidation. Increased fatty acid flux or enforced CD36 expression in C(2)C(12) cells is sufficient to induce FoxO1 and PDK4, whereas CD36 knockdown has opposite effects. In vivo, CD36 loss blunts fasting induction of FoxO1 and PDK4 and the associated suppression of glucose oxidation. Importantly, CD36-dependent regulation of FoxO1 is mediated by the nuclear receptor PPARdelta/beta. Loss of PPARdelta/beta phenocopies CD36 deficiency in blunting fasting induction of muscle FoxO1 and PDK4 in vivo. Expression of PPARdelta/beta in C(2)C(12) cells, like that of CD36, robustly induces FoxO1 and suppresses glucose oxidation, whereas co-expression of a dominant negative PPARdelta/beta compromises FoxO1 induction. Finally, several PPRE sites were identified in the FoxO1 promoter, which was responsive to PPARdelta/beta. Agonists of PPARdelta/beta were sufficient to confer responsiveness and transactivate the heterologous FoxO1 promoter but not in the presence of dominant negative PPARdelta/beta. Taken together, our findings suggest that CD36-dependent FA activation of PPARdelta/beta results in the transcriptional regulation of FoxO1 as well as PDK4, recently shown to be a direct PPARdelta/beta target. FoxO1 in turn can regulate CD36, lipoprotein lipase, and PDK4, reinforcing the action of PPARdelta/beta to increase muscle reliance on FA. The findings could have implications in the chronic abnormalities of fatty acid metabolism associated with obesity and diabetes.

SUBMITTER: Nahle Z

PROVIDER: S-EPMC2386936 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

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CD36-dependent regulation of muscle FoxO1 and PDK4 in the PPAR delta/beta-mediated adaptation to metabolic stress.

Nahlé Zaher Z Hsieh Michael M Pietka Terri T Coburn Chris T CT Grimaldi Paul A PA Zhang Michael Q MQ Das Debopriya D Abumrad Nada A NA

The Journal of biological chemistry 20080228 21

The transcription factor FoxO1 contributes to the metabolic adaptation to fasting by suppressing muscle oxidation of glucose, sparing it for glucose-dependent tissues. Previously, we reported that FoxO1 activation in C(2)C(12) muscle cells recruits the fatty acid translocase CD36 to the plasma membrane and increases fatty acid uptake and oxidation. This, together with FoxO1 induction of lipoprotein lipase, would promote the reliance on fatty acid utilization characteristic of the fasted muscle. ...[more]

PMID: 18308721

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Project description:BACKGROUND & AIMS:Although the role of inflammation to combat infection is known, the contribution of metabolic changes in response to sepsis is poorly understood. Sepsis induces the release of lipid mediators, many of which activate nuclear receptors such as the peroxisome proliferator-activated receptor (PPAR)?, which controls both lipid metabolism and inflammation. We aimed to elucidate the previously unknown role of hepatic PPAR? in the response to sepsis. METHODS:Sepsis was induced by intraperitoneal injection of Escherichia coli in different models of cell-specific Ppara-deficiency and their controls. The systemic and hepatic metabolic response was analyzed using biochemical, transcriptomic and functional assays. PPAR? expression was analyzed in livers from elective surgery and critically ill patients and correlated with hepatic gene expression and blood parameters. RESULTS:Both whole body and non-hematopoietic Ppara-deficiency in mice decreased survival upon bacterial infection. Livers of septic Ppara-deficient mice displayed an impaired metabolic shift from glucose to lipid utilization resulting in more severe hypoglycemia, impaired induction of hyperketonemia and increased steatosis due to lower expression of genes involved in fatty acid catabolism and ketogenesis. Hepatocyte-specific deletion of PPAR? impaired the metabolic response to sepsis and was sufficient to decrease survival upon bacterial infection. Hepatic PPARA expression was lower in critically ill patients and correlated positively with expression of lipid metabolism genes, but not with systemic inflammatory markers. CONCLUSION:During sepsis, Ppara-deficiency in hepatocytes is deleterious as it impairs the adaptive metabolic shift from glucose to FA utilization. Metabolic control by PPAR? in hepatocytes plays a key role in the host defense against infection. LAY SUMMARY:As the main cause of death in critically ill patients, sepsis remains a major health issue lacking efficacious therapies. While current clinical literature suggests an important role for inflammation, metabolic aspects of sepsis have mostly been overlooked. Here, we show that mice with an impaired metabolic response, due to deficiency of the nuclear receptor PPAR? in the liver, exhibit enhanced mortality upon bacterial infection despite a similar inflammatory response, suggesting that metabolic interventions may be a viable strategy for improving sepsis outcomes.

Dataset Information

CD36-dependent regulation of muscle FoxO1 and PDK4 in the PPAR delta/beta-mediated adaptation to metabolic stress.

Publications

CD36-dependent regulation of muscle FoxO1 and PDK4 in the PPAR delta/beta-mediated adaptation to metabolic stress.

Similar Datasets

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