Metabolic Targets in Nonalcoholic Steatohepatitis: Treating the Disease at the Metabolic Root
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FATTY LIVER DISEASE (V AJMERA, SECTION EDITOR)
Metabolic Targets in Nonalcoholic Steatohepatitis: Treating the Disease at the Metabolic Root Pankaj Aggarwal 1
&
Tamneet Singh 1 & Naim Alkhouri 1,2
# Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Purpose of Review Nonalcoholic fatty liver disease (NAFLD) and its more aggressive form nonalcoholic steatohepatitis (NASH) are a leading cause of chronic liver disease worldwide. Thus far, there are no FDA-approved therapeutic options for NASH. This review discusses relevant and recent findings in the development of pharmacotherapy that targets the metabolic processes implicated in NASH. Recent Findings Several key drugs have been identified across various drug classes. Among inhibitors of de novo lipogenesis, the SCD-1 inhibitor aramchol and the ACC inhibitor firsocostat are the most advanced. Within nuclear hormone receptor agonists, PPARα/δ agonist elafibranor and PPARα/γ agonist saroglitazar show promise with respect to improvement in NASH histology and hepatic steatosis. Additionally, THR-β agonist resmetirom showed significant reduction in hepatic steatosis and NASH resolution. Larger studies with longer treatment duration are needed to establish safety and efficacy of these metabolic drugs. Summary Significant progress has been made over the past decade in testing drugs that modulate the metabolic targets responsible for NASH progression. Keywords Nonalcoholic fatty liver disease . Nonalcoholic steatohepatitis . Diabetes mellitus . Obesity . Metabolic syndrome
Introduction Nonalcoholic fatty liver disease (NAFLD) has become one of the most common causes for chronic liver disease worldwide. Likely related to the rise in obesity and metabolic syndrome, NAFLD is now the second most common cause of liver transplant and hepatocellular carcinoma in the United States [1, 2]. In a large meta-analysis by Younossi et al., the global prevalence of NAFLD was estimated to be approximately 25%— the vast majority of whom have metabolic syndrome. In the United States, NAFLD is seen in up to 75 million people [3]. NAFLD is a spectrum that ranges from (1) fatty liver disease, characterized by progressive fatty infiltration of the liver This article is part of the Topical Collection on Fatty Liver Disease * Naim Alkhouri [email protected] 1
University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA
2
The Texas Liver Institute, University of Texas Health San Antonio, 607 Camden Street, San Antonio, TX 78215s, USA
parenchyma; (2) nonalcoholic steatohepatitis (NASH), characterized by the development of inflammation and hepatocyte injury in the form of ballooning; (3) progressive liver fibrosis; and (4) eventual cirrhosis with associated complications [4]. The histologic severity of NAFLD is determined by the NAFLD activity score (NAS) which is a semiquantitative grading system for the main histologic features of steatosis, lobular inflammation, and ballooning [5]. Currently, there are no pharmacotherapeutic options approved
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