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Fatty acids regulate CREBh via transcriptional mechanisms that are dependent on proteasome activity and insulin

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Abstract

Excess fatty acids are closely associated with metabolic dysfunction. The deleterious effects of fatty acids relate, in part, to their ability to up-regulate pro-inflammatory cytokines and propagate a state of systemic inflammation. CREBh is a recently identified transcription factor that appears to be required for hepatic synthesis of C-reactive protein. Recent data suggest that fatty acids can up-regulate CREBh, thus establishing a potential molecular link between fatty acids and inflammation. The aim of this study was to examine the nature and mechanisms of fatty acid-mediated regulation of CREBh. H4IIE liver cells were incubated in the absence or presence of varying concentrations (50–500 μM) of albumin-bound, long-chain saturated (palmitate, stearate) or unsaturated (oleate, linoleate) fatty acids (1–16 h). All fatty acids significantly increased CREBh gene expression via transcriptional mechanisms, at concentrations as low as 50 μM. Palmitate- or oleate-mediated up-regulation of CREBh was not inhibited by triacsin C, an inhibitor of long-chain fatty acyl CoA synthetase, or by the PPARα antagonist, MK886. Inhibition of proteasome activity with MG132 or lactacystin, or inclusion of insulin reduced palmitate- and oleate-mediated increases in CREBh mRNA. Finally, we examined fatty acid regulation of CREBh in vivo. Male Wistar rats were exposed to a 4-h pancreatic clamp combined with infusion of saline or a mixed lipid emulsion. CREBh mRNA and protein were significantly increased in rats exposed to the lipid infusion compared to the saline group. Collectively, these results may have important implications for metabolic diseases characterized by excess fatty acids, insulin resistance, and inflammation.

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Acknowledgments

This study was supported by National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) grants DK-072017 and DK-47416, and the Lillian Fountain Smith Foundation Endowment. CLG was supported by an individual postdoctoral fellowship, NIDDK F32DK082166-01.

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Correspondence to Michael J. Pagliassotti.

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Gentile, C.L., Wang, D., Pfaffenbach, K.T. et al. Fatty acids regulate CREBh via transcriptional mechanisms that are dependent on proteasome activity and insulin. Mol Cell Biochem 344, 99–107 (2010). https://doi.org/10.1007/s11010-010-0533-3

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