Selenoprotein P (SeP; encoded by SELENOP in humans, Selenop in rodents) is a hepatokine that is upregulated in the liver of humans with type 2 diabetes. Excess SeP contributes to the onset of insulin resistance and various type 2 diabetes-related complications. We have previously reported that the long-chain saturated fatty acid, palmitic acid, upregulates Selenop expression, whereas the polyunsaturated fatty acids (PUFAs) downregulate it in hepatocytes. However, the effect of medium-chain fatty acids (MCFAs) on Selenop is unknown. Here we report novel mechanisms that underlie the lauric acid-mediated Selenop gene regulation in hepatocytes. Lauric acid upregulated Selenop expression in Hepa1-6 hepatocytes and mice liver. A luciferase promoter assay and computational analysis of transcription factor-binding sites identified the hepatic nuclear factor 4α (HNF4α) binding site in the SELENOP promoter. A chromatin immunoprecipitation (ChIP) assay showed that lauric acid increased the binding of HNF4α to the SELENOP promoter. The knockdown of Hnf4α using siRNA canceled the upregulation of lauric acid-induced Selenop. Thus, the lauric acid-induced impairment of Akt phosphorylation brought about by insulin was rescued by the knockdown of either Hnf4α or Selenop. These results provide new insights into the regulation of SeP by fatty acids and suggest that SeP may mediate MCFA-induced hepatic insulin signal reduction.
Selenoprotein P is upregulated in type 2 diabetes, causing insulin and exercise resistance. We have previously reported that eicosapentaenoic acid (EPA) negatively regulates Selenop expression by suppressing Srebf1 in H4IIEC3 hepatocytes. However, EPA downregulated Srebf1 long before downregulating Selenop. Here, we report additional novel mechanisms for the Selenop gene regulation by EPA. EPA upregulated Foxo1 mRNA expression, which was canceled with the ERK1/2 inhibitor, but not with the PKA inhibitor. Foxo1 knockdown by siRNA initiated early suppression of Selenop, but not Srebf1, by EPA. However, EPA did not affect the nuclear translocation of the FoxO1 protein. Neither ERK1/2 nor PKA inhibitor affected FoxO1 nuclear translocation. In summary, FoxO1 knockdown accelerates the EPA-mediated Selenop downregulation independent of SREBP-1c in hepatocytes. EPA upregulates Foxo1 mRNA via the ERK1/2 pathway without altering its protein and nuclear translocation. These findings suggest redundant and conflicting transcriptional networks in the lipid-induced redox regulation.
The number of the words in the discussion: 843 Abbreviation: forkhead box protein O1 (FoxO1); signal transducer and activator of transcription 3 (STAT3); reactive oxygen species (ROS); sterol regulatory element-binding transcription factor 1c (SREBP-1c); hepatocyte nuclear factor 4 alpha (HNF4A); retinoic-acid-inducible gene I (RIG-I)
Muscle atrophy is the cause and consequence of obesity. Proteasome dysfunction mediates obesity-induced endoplasmic reticulum (ER) stress and insulin resistance in the liver and adipose tissues. However, obesity-associated regulation of proteasome function and its role in the skeletal muscles remains under-investigated. Here, we established skeletal muscle-specific 20S proteasome assembly chaperone-1 (PAC1) knockout (mPAC1KO) mice. A high-fat diet (HFD) activated proteasome function by ∼8 fold in the skeletal muscles, which was reduced by 50% in mPAC1KO mice. mPAC1KO induced unfolded protein responses in the skeletal muscles, which were reduced by HFD. Although the skeletal muscle mass and functions were not different between the genotypes, genes involved in the ubiquitin proteasome complex, immune response, endoplasmic stress, and myogenesis were coordinately upregulated in the skeletal muscles of mPAC1KO mice. Therefore, we introduced an immobilization-induced muscle atrophy model in obesity by combining HFD and immobilization. mPAC1KO downregulated atrogin-1 and MuRF1, together with their upstream Foxo1 and Klf15, and protected against disused skeletal muscle mass reduction. In conclusion, obesity elevates proteasome functions in the skeletal muscles. PAC1 deficiency protects mice from immobilization-induced muscle atrophy in obesity. These findings suggest obesity-induced proteasome activation as a possible therapeutic target for immobilization-induced muscle atrophy.
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