Barragan Avila, J. E. | Search bioRxiv

bioRxiv2023

Beneficial effects of intermittent fasting in NASH and subsequent HCC development are executed by concerted PPAR alpha and PCK1 action in hepatocytes

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/ameliorates NASH and fibrosis as well as reduces subsequent HCC development without affecting total calorie intake. The timing, length and number of fasting cycles as well as the type of NASH diet were all critical parameters determining the effectiveness of the fasting benefits. Combined proteomic, transcriptomic and metabolomic analyses identified that PPAR and glucocorticoid receptor (GR)-PCK1 act co-operatively as hepatic executors of the fasting response by promoting fatty acid catabolism and gluconeogenesis whilst suppressing anabolic lipogenesis. In line, PPAR targets and PCK1 were reduced in human NASH. Additionally, dynamic [18F]FDG-PET analysis in vivo revealed increased [18F]FDG uptake/retention and enhanced gluconeogenesis in the liver upon fasting (in accordance with PPAR and GR-PCK1 activation) when assessed by compartmental modelling. Hepatocyte-specific GR deletion only partially abrogated the hepatic fasting response. In contrast, 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. Notably, PPAR agonist pemafibrate recapitulated key aspects of hepatic fasting signalling at a molecular level. Therefore, IF or pharmacological mimetics of the PPAR and/or GR-PCK1 axis could be a viable intervention against NASH and subsequent liver cancer. One-Sentence SummaryIntermittent fasting protects against fatty liver disease and liver cancer through concerted PPAR and GR-PCK1 action in hepatocytes.

cancer biology↗

bioRxiv2023

Ribosomal S6 kinase 1 regulates inflammaging via the senescence secretome

Inhibition of the nutrient-responsive mTOR (mammalian target of rapamycin) signalling pathway including the key downstream effector S6 kinase 1 (S6K1) extends lifespan and improves healthspan in mice. However, the underlying mechanisms contributing to the broad range of age-related benefits observed with loss of S6K1 signalling are unclear. Cellular senescence is a stable growth arrest accompanied by an inflammatory phenotype (termed the senescence-associated secretory phenotype, or SASP). While both cellular senescence and SASP-mediated chronic inflammation contribute to age-related pathology, the specific role of S6K1 signalling in these processes has not been determined. Here, focussing on mouse liver, a key target tissue for the beneficial metabolic effects of loss of S6K1 signalling, we show that S6K1 deletion does not reduce senescence but ameliorates inflammation and immune cell infiltration in aged livers. Using human and mouse models of senescence, we demonstrated that reduced inflammation is a liver-intrinsic effect associated with S6K deletion. Furthermore, gene expression analysis suggested that downregulated cGAS/STING and IRF3 activation might mediate the impaired SASP observed upon S6K deletion. Using a hepatic oncogene induced senescence model, we showed in vivo that S6K1 deletion results in reduced IRF3 activation, impaired production of cytokines such as IL1y and reduced immune infiltration. Overall, deletion of S6K reduces inflammation in the liver suggesting that suppression of the inflammatory SASP by loss of S6K could contribute to explain the beneficial effects of inhibiting this pathway on healthspan and lifespan.

physiology↗