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Semin Liver Dis 2020; 40(04): 346-357
DOI: 10.1055/s-0040-1713115
Review Article

Nonalcoholic Steatohepatitis Promoting Kinases

Samar H. Ibrahim
1   Division of Gastroenterology & Hepatology in the Department of Pediatrics, Medicine Mayo Clinic, Rochester, Minnesota
2   Division of Gastroenterology & Hepatology in the Department of Medicine Mayo Clinic, Rochester, Minnesota
,
Petra Hirsova
2   Division of Gastroenterology & Hepatology in the Department of Medicine Mayo Clinic, Rochester, Minnesota
,
Harmeet Malhi
2   Division of Gastroenterology & Hepatology in the Department of Medicine Mayo Clinic, Rochester, Minnesota
,
Gregory J. Gores
2   Division of Gastroenterology & Hepatology in the Department of Medicine Mayo Clinic, Rochester, Minnesota
› Author Affiliations Funding Funding support from the AASLD Foundation Bridge Award (to SHI), the NIH grant DK111397 (to SHI), Gilead Science career development award (to SHI), and the Mayo Clinic K2R pipeline (to SHI); NIH grant DK41876 (to GJG); Mayo Clinic Center for Cell Signaling in Gastroenterology (NIDDK P30DK084567) Pilot and Feasibility Award (to PH); NIH grant DK11378 (to HM); and the Mayo Foundation.
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Abstract

Nonalcoholic hepatitis (NASH) is the progressive inflammatory form of nonalcoholic fatty liver disease. Although the mechanisms of hepatic inflammation in NASH remain incompletely understood, emerging literature implicates the proinflammatory environment created by toxic lipid-induced hepatocyte injury, termed lipotoxicity. Interestingly, numerous NASH-promoting kinases in hepatocytes, immune cells, and adipocytes are activated by the lipotoxic insult associated with obesity. In the current review, we discuss recent advances in NASH-promoting kinases as disease mediators and therapeutic targets. The focus of the review is mainly on the mitogen-activated protein kinases including mixed lineage kinase 3, apoptosis signal-regulating kinase 1, c-Jun N-terminal kinase, and p38 MAPK; the endoplasmic reticulum (ER) stress kinases protein kinase RNA-like ER kinase and inositol-requiring protein-1α; as well as the Rho-associated protein kinase 1. We also discuss various pharmacological agents targeting these stress kinases in NASH that are under different phases of development.

Keywords

mitogen-activated protein kinases - Rho-associated protein kinase - endoplasmic reticulum stress - nonalcoholic steatohepatitis


Publication History

Article published online:
11 June 2020

© 2020. Thieme. All rights reserved.

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