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Davuluri G, Welch N, Sekar J, et al. Activated Protein Phosphatase 2A Disrupts Nutrient Sensing Balance Between Mechanistic Target of Rapamycin Complex 1 and Adenosine Monophosphate-Activated Protein Kinase, Causing Sarcopenia in Alcohol-Associated Liver Disease. Hepatology. 2021;73(5):1892-1908doi: 10.1002/hep.31524.
Davuluri, G., Welch, N., Sekar, J., Gangadhariah, M., Alsabbagh Alchirazi, K., Mohan, M. L., Kumar, A., Kant, S., Thapaliya, S., Stine, M., McMullen, M. R., McCullough, R. L., Stark, G. R., Nagy, L. E., Naga Prasad, S. V., & Dasarathy, S. (2021). Activated Protein Phosphatase 2A Disrupts Nutrient Sensing Balance Between Mechanistic Target of Rapamycin Complex 1 and Adenosine Monophosphate-Activated Protein Kinase, Causing Sarcopenia in Alcohol-Associated Liver Disease. Hepatology (Baltimore, Md.), 73(5), 1892-1908. https://doi.org/10.1002/hep.31524
Davuluri, Gangarao, et al. "Activated Protein Phosphatase 2A Disrupts Nutrient Sensing Balance Between Mechanistic Target of Rapamycin Complex 1 and Adenosine Monophosphate-Activated Protein Kinase, Causing Sarcopenia in Alcohol-Associated Liver Disease." Hepatology (Baltimore, Md.) vol. 73,5 (2021): 1892-1908. doi: https://doi.org/10.1002/hep.31524
Davuluri G, Welch N, Sekar J, Gangadhariah M, Alsabbagh Alchirazi K, Mohan ML, Kumar A, Kant S, Thapaliya S, Stine M, McMullen MR, McCullough RL, Stark GR, Nagy LE, Naga Prasad SV, Dasarathy S. Activated Protein Phosphatase 2A Disrupts Nutrient Sensing Balance Between Mechanistic Target of Rapamycin Complex 1 and Adenosine Monophosphate-Activated Protein Kinase, Causing Sarcopenia in Alcohol-Associated Liver Disease. Hepatology. 2021 May;73(5):1892-1908. doi: 10.1002/hep.31524. Epub 2021 Apr 20. PMID: 32799332.
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Hepatology. 2021 May;73(5):1892-1908. doi: 10.1002/hep.31524. Epub 2021 Apr 20.

Activated Protein Phosphatase 2A Disrupts Nutrient Sensing Balance Between Mechanistic Target of Rapamycin Complex 1 and Adenosine Monophosphate-Activated Protein Kinase, Causing Sarcopenia in Alcohol-Associated Liver Disease.

Hepatology (Baltimore, Md.)

Gangarao Davuluri, Nicole Welch, Jinendiran Sekar, Mahesha Gangadhariah, Khaled Alsabbagh Alchirazi, Maradumane L Mohan, Avinash Kumar, Sashi Kant, Samjhana Thapaliya, McKenzie Stine, Megan R McMullen, Rebecca L McCullough, George R Stark, Laura E Nagy, Sathyamangla V Naga Prasad, Srinivasan Dasarathy

Affiliations

  1. Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH.
  2. Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH.
  3. Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland, OH.
  4. Department of Cancer Biology, Cleveland Clinic, Cleveland, OH.

PMID: 32799332 DOI: 10.1002/hep.31524

Abstract

BACKGROUND AND AIMS: Despite the high clinical significance of sarcopenia in alcohol-associated cirrhosis, there are currently no effective therapies because the underlying mechanisms are poorly understood. We determined the mechanisms of ethanol-induced impaired phosphorylation of mechanistic target of rapamycin complex 1 (mTORC1) and adenosine monophosphate-activated protein kinase (AMPK) with consequent dysregulated skeletal muscle protein homeostasis (balance between protein synthesis and breakdown).

APPROACH AND RESULTS: Differentiated murine myotubes, gastrocnemius muscle from mice with loss and gain of function of regulatory genes following ethanol treatment, and skeletal muscle from patients with alcohol-associated cirrhosis were used. Ethanol increases skeletal muscle autophagy by dephosphorylating mTORC1, circumventing the classical kinase regulation by protein kinase B (Akt). Concurrently and paradoxically, ethanol exposure results in dephosphorylation and inhibition of AMPK, an activator of autophagy and inhibitor of mTORC1 signaling. However, AMPK remains inactive with ethanol exposure despite lower cellular and tissue adenosine triphosphate, indicating a "pseudofed" state. We identified protein phosphatase (PP) 2A as a key mediator of ethanol-induced signaling and functional perturbations using loss and gain of function studies. Ethanol impairs binding of endogenous inhibitor of PP2A to PP2A, resulting in methylation and targeting of PP2A to cause dephosphorylation of mTORC1 and AMPK. Activity of phosphoinositide 3-kinase-γ (PI3Kγ), a negative regulator of PP2A, was decreased in response to ethanol. Ethanol-induced molecular and phenotypic perturbations in wild-type mice were observed in PI3Kγ

CONCLUSIONS: Our study describes the mechanistic underpinnings for ethanol-mediated dysregulation of protein homeostasis by PP2A that leads to sarcopenia with a potential for therapeutic approaches by targeting the PI3Kγ-PP2A axis.

© 2020 by the American Association for the Study of Liver Diseases.

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