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Renal tubular Pck1 knockout mice showed albuminuria.

ABSTRACT: We aim to investigate the role of renal Pck1 on albuminuria. To further development of our gene expression approach to biodosimetry, we have employed whole genome microarray expression profiling as a discovery platform to identify genes with the potential to distinguish between wild type mice. To elucidate the molecular mechanisms underlying the increase in albuminuria by our Pck-CKO (Pck1 conditional knockout) mice, we performed DNA microarray analysis using whole kidneys to examine the differences in gene expression between Pck1-CKO and wild-type control mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE228053 | GEO | 2023/03/29

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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Renal tubular Pck1 knockout mice showed albuminuria.

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