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

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 ?M) 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 ?M. 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 PPAR? 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.

SUBMITTER: Gentile CL

PROVIDER: S-EPMC3045845 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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

Gentile C L CL Wang D D Pfaffenbach K T KT Cox R R Wei Y Y Pagliassotti Michael J MJ

Molecular and cellular biochemistry 20100704 1-2

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. ...[more]

PMID: 20607591

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

Publications

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

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