From the AGA Journals

Liver protein protects against parenteral nutrition liver injury

New findings may lead to novel treatments

Parenteral nutrition is a life saver for children and adults with insufficient absorptive capacity of the gastrointestinal tract. Unfortunately, up to two-thirds of patients requiring parenteral nutrition long-term develop liver disease, which can have fatal outcomes. Parenteral nutrition–associated liver disease is characterized by fibrosis and steatosis. While portal inflammation and cholestasis resolve in patients who can be weaned off parenteral nutrition, portal fibrosis and steatosis unfortunately remain in about half of the patients. The development of therapeutic strategies for this condition has thus far been hampered by the fact that the molecular mechanism of parenteral nutrition–associated liver disease was unknown.

This study by Maitiabua and colleagues from Nanjing University Medical School addresses this problem by performing a proteomic and, importantly, phospho-proteomic analysis of liver biopsies from adults treated with parenteral nutrition compared to normally-feeding controls. They discovered that levels of phosphorylated AKT2, the key signaling mediator of insulin in the liver, are increased, while protein levels of the opposing protein phosphatase 2A (PP2A) are decreased in patients receiving parenteral nutrition.

Remarkably, they could reproduce these same pathway changes in a mouse model of parenteral nutrition, which again led to a chronic activation of the insulin signaling pathway, culminating in the phosphorylation of AKT2. They show further that activation of AKT2 inhibits AMPK and alters hepatic lipid metabolism to promote triglyceride accumulation. Using the experimentally tractable mouse model, they demonstrate further that the ablation of a PP2A isoform in the liver is sufficient to cause lipid accumulation and liver injury. Conversely, restoring PP2A expression improved the hepatic phenotype in mice in the parenteral nutrition model. These findings could also be mimicked using pharmacological activation and inhibition of PP2A.

In sum, this experimental study could some day lead the way to novel treatments of parenteral nutrition-induced liver disease through the use of PP2A activators.

Klaus H. Kaestner, PhD, is with the department of genetics and Center for Molecular Studies in Digestive and Liver Diseases, Perelman School of Medicine,University of Pennsylvania, Philadelphia.


 

FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY

Hepatic protein PP2A-C-alpha may serve as a protective factor against parenteral nutrition–associated hepatic steatosis by improving liver function, according to a recent study published in Cellular and Molecular Gastroenterology and Hepatology.

Parenteral nutrition–associated hepatic steatosis likely involves the down-regulation of hepatic PP2A-C-alpha and consequent increased phosphorylation of Akt2; this in turn alters hepatic lipid metabolism, promotes triglyceride accumulation, and leads to liver injury, wrote the researchers, led by Gulisudumu Maitiabula and Feng Tian of the Research Institute of General Surgery at Jinling Hospital, Nanjing, China, and the Medical School of Nanjing University.

“Our study provides a strong rationale that PP2A-C-alpha may be involved in the pathogenesis of [parenteral nutrition–associated hepatic steatosis],” they wrote. “Further research is merited to establish whether interventions to enhance PP2A function might suppress the development of hepatic steatosis in patients receiving long-term [parenteral nutrition].”

Parenteral nutrition can be a lifesaving therapy for patients with intestinal failure caused by insufficient bowel length or function, the authors noted However, long-term use can lead to potentially fatal complications such as liver disease, but an understanding of the pathological mechanisms behind parenteral nutrition–associated hepatic steatosis limited.

The research team performed comparative proteomic/phosphoproteomic analyses of liver samples from 10 patients with parenteral nutrition–associated hepatic steatosis, as well as 8 cholelithiasis patients as controls, who were admitted to Jinling Hospital between June 2018 and June 2019. The researchers also assessed the effect of PP2A-C-alpha on liver injury from total parenteral nutrition in mice.

The research team found that PP2A-C-alpha was down-regulated in patients and mice with parenteral nutrition–associated hepatic steatosis. In addition, in patients with parenteral nutrition–associated hepatic steatosis, they found enhanced activation of serine/threonine kinase Akt2 and decreased activation of AMPK.

Mice that were given total parenteral nutrition infusion 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 parenteral nutrition exacerbated the Akt2 activation, AMPK inhibition, and hepatic steatosis through an effect on fatty acid degradation.

On the other hand, forced expression of PP2A-C-alpha led to reductions in hepatocyte fat deposition and the pathological score for liver steatosis. Overexpression also significantly improved hepatic steatosis, suppressed Akt2, and activated AMPK. In addition, pharmacological activation of Akt2 in mice overexpressing PP2A-C-alpha led to the aggravation of hepatic steatosis.

“Collectively, these observations suggest that [parenteral nutrition] for [more than] 14 days leads to a down-regulation in PP2A-C-alpha expression that activates Akt2-dependent signaling, which would likely lead to hepatic steatosis,” the study authors wrote.

Intervention trials of PP2A-C-alpha in humans have not been performed because PP2A-C-alpha activators or effector analogs were unavailable for clinical use, they wrote. Additional clinical studies are needed to investigate the effects of PP2A-C-alpha intervention on the development of hepatic steatosis in patients receiving long-term parenteral nutrition.

The study was supported by the National Natural Science Foundation of China, the Science Foundation of Outstanding Youth in Jiangsu Province, the National Science and Technology Research Funding for Public Welfare Medical Projects, “The 13th Five-Year Plan” Foundation of Jiangsu Province for Medical Key Talents, and the Natural Science Foundation of Jiangsu Province. The study authors disclosed no conflicts of interest.

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