Liver PP2A-C alpha Protects From Parenteral Nutrition- associated Hepatic Steatosis

BACKGROUND & AIMS: Parenteral nutrition (PN) is a life-saving therapy for patients with intestinal failure. Hepatic steatosis is a potentially fatal complication of long-term PN, but the involved pathological mechanisms are incompletely un-clarified. Herein, we identify the role of protein phosphatase 2A (PP2A) in the pathogenesis of parenteral nutrition-associated hepatic steatosis (PNAHS). METHODS: Proteomic/phosphoproteomic analyses of liver samples from patients with PNAHS were applied to identify the mechanism of PNAHS. Total parenteral nutrition (TPN) mice model, in vivo, and in vitro experiments were used to assess the effect of PP2A-C alpha on liver fatty acid metabolism. RESULTS: Reduced expression of PP2A-C alpha (catalytic subunit) enhanced activation of serine/threonine kinase Akt2 and decreased activation of adenosine monophosphate-activated protein kinase (AMPK) were associated with hepatic steatosis in patients with PNAHS. Mice given PN for 14 days developed hepatic steatosis, down-regulation of PP2A-C alpha, activation of Akt2, and inhibition of AMPK. Hepatocyte-specific deletion of PP2A-C alpha in mice given PN exacerbated Akt2 activation, AMPK inhibition, and hepatic steatosis through an effect on fatty acid degradation, whereas hepatocyte-specific PP2A-C alpha overexpression significantly ameliorated hepatic steatosis accompanied with Akt2 suppression and AMPK activation. Additionally, pharmacological activation of Akt2 in mice overexpressing PP2A-C alpha led to the aggravation of hepatic steatosis. CONCLUSIONS: Our findings demonstrate that hepatic PP2A-C alpha serves as a protective factor of PNAHS due to ameliorating hepatic steatosis and improving liver function. Our study provides a strong rationale that PP2A-C alpha may be involved in the pathogenesis of PNAHS.

Automated summary

PP2A-Cα plays an important role in the pathogenesis of PNAHS, acting as a protective factor by improving hepatic steatosis and liver function. A decrease in PP2A-Cα leads to activation of Akt2 and inhibition of AMPK, exacerbating hepatic steatosis.