Holm, E. | bioRxiv Science

bioRxiv2024

AMPK-activator ATX-304 reduces oxidative stress and improves MASLD via metabolic switching

AbstractMetabolic dysfunction-Associated Steatotic Liver Disease (MASLD) is the most common chronic liver disease worldwide for which there are no approved treatments. Adenosine monophosphate-activated protein kinase (AMPK) is an interesting therapeutical target since it acts as a central regulator of cellular metabolism. Despite efforts to target the AMPK, no direct activators has yet been approved for treatment of this disease. This study investigates the effect of AMPK activator ATX-304 in a preclinical mouse model of progressive fatty liver disease. The data demonstrate that ATX-304 diminishes body fat mass, lowers blood cholesterol levels, mitigates liver steatosis, and ameliorates the development of liver fibrosis. The beneficial effects of ATX-304 treatment are accompanied by a shift in the liver metabolic program, including increased lipid oxidation, reduced lipid synthesis, as well as remodeling of cholesterol and lipid transport. We also observed variations in lipid distribution among liver lobes in response to ATX-304, and a shift in the zonal distribution of lipid droplets upon treatment. Taken together, our data suggest that ATX-304 holds promise as a potential treatment for Metabolically Associated Fatty Liver Disease (MAFLD), including in human patients.

molecular biology↗

bioRxiv2022

Lamin A/C phosphorylation at serine 22 is a conserved heat shock response to regulate nuclear adaptation during stress

The heat shock (HS) response is crucial for cell survival in harmful environments. Nuclear lamin A/C, encoded by LMNA gene, has been shown to contribute towards altered gene expression during heat shock, but the underlying mechanisms are poorly understood. Here we show that reversible lamin A/C phosphorylation at Ser22 upon HS is an evolutionary conserved stress response that is triggered in concert with HSF1 activation in human and mouse cells and can also be observed in D. melanogaster in vivo. Consequently, the phosphorylation increase facilitated nucleoplasmic localization of lamin A/C and nuclear rounding in response to HS. The importance of lamin phosphorylation equilibria in HS was confirmed by lamin A/C knock-out (KO) cells that showed deformed nuclei after HS and were rescued by ectopic expression of wild-type, but not by a phosphomimetic (S22D) lamin A mutant. Furthermore, HS triggered release of lamina-associated protein 2 (Lap2) from its association with lamin A/C and concurrently its downregulation, a response that was perturbed in lamin A/C KO cells and in LMNA mutant patient fibroblasts. The abrogated Lap2 response resulted in impaired cell cycle arrest under HS and compromised survival at the recovery. Taken together, our results suggest that the altered phosphorylation stoichiometry of lamin A/C provides an evolutionary conserved mechanism to regulate lamin structure and serve nuclear adaptation and cell survival during HS.

molecular biology↗