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Modulation of AKAP12 in the liver regulates lipid homeostasis and inflammation

ABSTRACT: 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

ORGANISM(S): Mus musculus

PROVIDER: GSE290266 | GEO | 2025/03/02

REPOSITORIES: GEO

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Project description:Fat accumulation, de novo lipogenesis, and glycolysis are key contributors to hepatocyte reprogramming and the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). The molecular mechanisms affected by steatosis and inflammation in the obese states remain unknown. Here we report that obesity leads to dysregulated expression of protein-tyrosine phosphatases (PTPs) in the liver. Protein Tyrosine Phosphatase Receptor Kappa (PTPRK) was increased in hepatocytes by steatosis and inflammation in humans and mice, and positively correlates with PPARγ-induced lipogenic signalling. Mechanistically, PTPRK-PPARγ upregulation by fat accumulation is dependent upon Notch signalling in mouse primary hepatocytes. PTPRK knockout mice have reduced fat accumulation in adipose tissue and liver after exposure to an obesogenic diet. Phosphoproteomic analysis in isolated hepatocytes and hepatic metabolomics identified specific phosphotyrosine residues in fructose-1,6 bisphosphatase-1 and glycolysis regulation as targets of PTPRK. These changes in glycolysis and de novo lipogenesis revealed PTPRK-dependent metabolic reprogramming in hepatocytes. Moreover, hepatoma cell lines showed reduced colony-forming ability after PTPRK silencing in vitro, and PTPRK knockout mice developed smaller tumours after diethylnitrosamine-induced hepatocarcinogenesis in vivo. Computational modelling identified potential PTPRK inhibitors, which selectively reduced PTPRK activity. The compounds decreased glycolytic rates in hepatoma cell lines, PPARγ expression in primary hepatocytes and steatosis in obese mice. In conclusion, our study defines a novel mechanism for the development of MASLD, revealing a key role of PTPRK on hepatic glycolysis regulation with implications in lipid metabolism, and liver tumour development. We propose PTPRK as a potential target for metabolic liver dysfunction, and the identified inhibitors may represent promising candidates for therapy in obesity-associated liver diseases.

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Modulation of AKAP12 in the liver regulates lipid homeostasis and inflammation

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