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SHP-1 regulates transcription of PCK1 to control gluconeogenesis

ABSTRACT: The protein-tyrosine phosphatase SHP-1 (PTPN6) is an important glucose homeostasis modulator. Besides negatively regulating insulin signaling, the specific role of SHP-1 in metabolic control remains poorly understood. We show that SHP-1 acts as a co-activator for transcription of the phosphoenolpyruvate carboxykinase 1 (PCK1) gene, thereby modulating basal gluconeogenesis in hepatocytes. SHP-1 interacts with RNA polymerase II-subunits and signal transducer and activator of transcription 5 (STAT5), and localizes to the nucleus, where a sub-fraction of SHP-1 associates with chromatin. While SHP-1 binds to the PCK1-promoter, its loss affects RNA polymerase II-recruitment to this and other promoters of genes enriched for glucose metabolism-related functions. SHP-1-downregulation, and similarly STAT5 pharmacological inhibition reduce PCK1-transcript levels correlating with blunted gluconeogenesis. Overall, we identified a novel molecular SHP-1-function, that of a regulator of PCK1-transcription and subsequently hepatic gluconeogenesis, through physical interaction with the transcription machinery, mediated by an Akt-independent mechanism, but independent of STAT5 tyrosine-phosphorylation status.

ORGANISM(S): Homo sapiens

PROVIDER: GSE174142 | GEO | 2023/09/08

REPOSITORIES: GEO

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Project description:The role and molecular mechanisms of intermittent fasting (IF) in non-alcoholic steatohepatitis (NASH) and its transition to hepatocellular carcinoma (HCC) are unknown. Here, we identified that an IF 5:2 regimen (two non-consecutive days of food deprivation per week), initiated in the active phase of mice, prevents NASH development as well as ameliorates established NASH and fibrosis without affecting total calorie intake. Furthermore, the IF 5:2 regimen also blunted NASH-HCC transition when applied therapeutically in two independent models of diet-induced NASH and NASH-HCC. The timing (7pm-7pm > 7am-7am), length (24h > 12h) and number (5:2 > 6:1) of fasting cycles as well as the type (WD / CDHFD) of NASH diet were all critical parameters determining the effectiveness of the fasting benefits. Combined proteome, transcriptome and metabolome analyses identified that PPARα and glucocorticoid signalling-induced phosphoenolpyruvate carboxykinase 1 (PCK1) act co-operatively as hepatic executors of the fasting response by promoting fatty acid catabolism and gluconeogenesis while suppressing anabolic lipogenesis. In line, PPARα targets and PCK1 were reduced in human NASH. Notably, only fasting during the active phase (7pm-7pm) of mice robustly induced glucocorticoid signalling in hepatocytes including PCK1 expression; while both active and inactive phase (7am-7am) fasting induced free fatty acid-induced PPARα signalling, highlighting the increased efficacy of fasting during the active phase. However, hepatocyte-specific glucocorticoid receptor (GR) deletion only partially abrogated the hepatic fasting response, illustrating the need for both glucocorticoid-induced PCK1 expression and free fatty acid-induced PPARα activation for mediating the benefits of fasting. In support, the combined knockdown of Ppara and Pck1 in vivo abolished the beneficial outcomes of fasting against inflammation and fibrosis, confirming their causal relationship in integrating systemic signalling in hepatocytes. Moreover, overexpression of Pck1 alone or together with Ppara in vivo lowered hepatic triglycerides and steatosis upon Western-diet feeding. Altogether, our data support that the IF 5:2 regimen could be a promising and viable intervention against NASH and subsequent liver cancer.

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SHP-1 regulates transcription of PCK1 to control gluconeogenesis

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