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Review
. 2024 Jul 1;80(1):223-237.
doi: 10.1097/HEP.0000000000000381. Epub 2023 Mar 21.

Emerging targets for therapy in ALD: Lessons from NASH

Ashwani K Singal  1   2   3 , Vijay H Shah  4 , Harmeet Malhi  4
Affiliations
Review

Emerging targets for therapy in ALD: Lessons from NASH

Ashwani K Singal et al. Hepatology. .

Abstract

Alcohol-associated liver disease due to harmful alcohol use and NAFLD associated with metabolic syndrome are the 2 most common liver diseases worldwide. Control of respective risk factors is the cornerstone in the long-term management of these diseases. Furthermore, there are no effective therapies. Both diseases are characterized by metabolic derangements; thus, the focus of this review was to broaden our understanding of metabolic targets investigated in NAFLD, and how these can be applied to alcohol-associated liver disease. Conserved pathogenic pathways such as dysregulated lipid metabolism, cell death pathways including apoptosis and activation of innate immune cells, and stellate cells mediate both alcohol and NAFLDs, resulting in histological abnormalities of steatosis, inflammation, fibrosis, and cirrhosis. However, pathways such as gut microbiome changes, glucose metabolism and insulin resistance, inflammatory signaling, and microRNA abnormalities are distinct in these 2 diseases. In this review article, we describe conserved and distinct pathogenic pathways highlighting therapeutic targets that may be of potential in both diseases and those that are unique to each disease.

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Conflict of interest statement

CONFLICTS OF INTEREST

Ashwani K. Singal consults for Pleiogenix Pharma. He advises Durect. Vijay H. Shah consults for Durect Corporation, GENFIT, Korro Bio Inc., and Seal Rock Therapeutics Inc. He advises Akaza Bioscience Ltd, AgomAb Therapeutics, Intercept Pharmaceuticals Inc., Mallinckrodt Pharmaceuticals, Resolution Therapeutics Ltd, and Surrozen. Harmeet Malhi has no conflicts to report.

Figures

FIGURE 1
FIGURE 1
Pathogenesis of alcohol-associated liver disease and alcoholic hepatitis. Abbreviations: DAMP, damage-associated molecular patterns; ER, endoplasmic reticulum; EV, extracellular vesicles; LPS, lipopolysaccharide; ROS, reactive oxygen species; TLR-4, toll-like receptor-4.
FIGURE 2
FIGURE 2
Pathogenesis of NAFLD. Abbreviations: ER, endoplasmic reticulum; EV, extracellular vesicles; FFA, free fatty acids; IRS, insulin receptor substrate; ROS, reactive oxygen species.
FIGURE 3
FIGURE 3
Mechanisms of alcohol induced increased hepatic triglyceride content and steatosis. Abbreviations: ER, endoplasmic reticulum; FFA, free fatty acids; TLR-4, toll-like receptor-4.
See this image and copyright information in PMC

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