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Alterations in alternative RNA splicing in hepatocytes from high-fat diet fed C57BL/6 male mice

ABSTRACT: Alterations in alternative RNA splicing in hepatocytes from high-fat diet fed C57BL/6 male mice

PROVIDER: PRJNA551398 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR9606504_1.fastq.gz	Fastqsanger.gz
	SRR9606504_2.fastq.gz	Fastqsanger.gz
	SRR9606505_1.fastq.gz	Fastqsanger.gz
	SRR9606505_2.fastq.gz	Fastqsanger.gz
	SRR9606506_1.fastq.gz	Fastqsanger.gz

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Project description:Protein kinase C epsilon (PKCe) has been shown to play a causative role in the generation of glucose intolerance and insulin resistance. Tissue-specific deletion of PKC indicates multiple sites of action, highlighting the kinase as a potential target for the treatment of type 2 diabetes. CIDD-0150612 has been developed as a PKCe inhibitor from the Rho-associated, coiled-coil containing protein kinase (ROCK) inhibitor Y-27632. Here, we examined the effects of a CIDD-0150612 on insulin action in palmitate-treated HepG2 hepatocytes in vitro and on glucose homeostasis in fat-fed mice in vivo. HepG2 cells were treated with palmitate and CIDD-0150612, and stimulated with insulin. Insulin signalling was examined by immunoblotting and glucose incorporation into glycogen was measured using glucose tracer. Mice were fed a high-fat diet for 8 weeks and treated with CIDD-0150612 in the final 2 weeks, prior to glucose tolerance tests, insulin challenge and tissue harvest. Proteomic and phosphoproteomic analysis was carried out on liver proteins by liquid chromatography with tandem mass spectrometry. CIDD-0150612 had no effect on insulin-stimulated insulin receptor or IRS-1 tyrosine phosphorylation in lipid-treated hepatocytes. However, the inhibitor promoted Akt phosphorylation in a highly insulin-dependent manner, and reversed the inhibition of insulin-stimulated Akt phosphorylation and glucose incorporation into glycogen by palmitate. Fat-fed mice treated with CIDD-0150612 had reduced body fat and body weight, but not lean mass, compared with vehicle-treated littermates. Mice treated acutely with CIDD-0150612 exhibited elevated fasting blood glucose. However, mice studied 24h after the last dose had lower fasting glucose and improved glucose tolerance with a lower insulin excursion. CIDD-0150612 treatment reduced skeletal muscle triglyceride content, but did not affect insulin signalling in liver or muscle in response to an insulin challenge. Proteomic analysis of liver from CIDD-0150612-treated fat-fed mice indicated a reduction in gluconeogenic gene expression and decreased phosphorylation of the transcription factor Foxk1. The PKCe inhibitor CIDD-0150612 had beneficial effects on insulin action in hepatocytes and on fat mass and glucose homeostasis in mice. Because certain effects, such as the reduction in fat mass, were not previously observed in studies of PKCe-deficient mice, off-target effects, most likely through residual ROCK1 inhibition, may be partly responsible.

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Alterations in alternative RNA splicing in hepatocytes from high-fat diet fed C57BL/6 male mice

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