Modulation of AKAP12 in the liver regulates lipid homeostasis and inflammation
Dysregulation of lipid homeostasis is a feature of alcohol-associated liver disease (ALD). A-kinase anchoring protein 12 (AKAP12) is a scaffolding partner of the cAMP-dependent protein kinase, PKA that controls its spatiotemporal localization. Activation of PKA by cAMP inhibits lipogenesis and facilitates fatty acid oxidation (FAO). We examined how AKAP12' could regulate alcohol-associated steatosis. Alcohol exposure reduced AKAP12's interaction with PKA and suppressed PKA activation. Forced expression of AKAP12 overcame the suppression of PKA activity in human hepatocytes and in livers of mice exposed to alcohol. This led to a decrease in hepatic steatosis. Disrupting the scaffold of AKAP12 and PKA by CRISPR editing increased steatosis and inflammation. RNA sequencing analysis of hepatocytes from alchol fed mice and normal mice demonstrated key lipogenic and inflammatory pathways regulated by AKAP12 overexpression. RNA sequencing of total liver from mice with AKAP12-PKA binding site CRISPR editing or AKAP12 overexpression confirmed regulation of lipogenic and inflammatory pathways by AKAP12 Overall design: (1) RNA sequencing profiling of hepatocytes from normal, alcohol-fed, normal+AKAP12 overexpression, alcohol+AKAP12 overexpression livers. (2) RNA sequencing profile of total liver from normal, alcohol-fed, normal+AKAP12-PKA CRISPR, alcohol-fed+AKAP12-PKA CRISPR, normal+AKAP12 overexpression, alcohol-fed+ AKAP12 overexpression mice.