The Impact of the NLRP3 Pathway in the Pathogenesis of Non-Alcoholic Fatty Liver Disease and Alcohol-Related Liver Disease

Lozan Sheriff,Patricia F Lalor

doi:10.3390/livers1020007

Abstract

The presence of hepatic steatosis and inflammation is increasingly associated with both metabolic and alcohol-related liver conditions. Both are on the increase globally and, apart from liver transplantation, there are no licensed therapies that target the full complement of disease features. The presence of some shared pathogenic mechanisms and histological features in NAFLD and ALD suggests that it may be possible to develop markers for prognostication or staging, or indeed new therapeutic tools to treat both conditions. One such example of an approach exists in the form of the NACHT-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome pathway. Activation of the NLRP3 inflammasome results in hepatocyte pyroptosis, persistence, and amplification of liver inflammation and activation of profibrogenic signaling cascades. Thus, targeting elements of the pathway in NAFLD and ALD may provide a tractable route to pharmacological therapy. In this review, we summarize the contribution of this inflammasome to disease and review the current options for therapy.

Highlights

The presence of hepatic steatosis and inflammation is increasingly associated with both metabolic and alcohol-related liver conditions
Both non-alcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ALD) are chronic conditions driven by multifactorial mechanisms
Non-alcoholic fatty liver disease exists as a spectrum from simple fatty liver injury to non-alcoholic steatohepatitis (NASH), fibrosis, and end-stage liver cirrhosis

Summary

Introduction

The presence of hepatic steatosis and inflammation is increasingly associated with both metabolic and alcohol-related liver conditions. 450% in the last 30 years [3], and alcohol-related liver disease is prevalent in European countries [4] In both situations, the causative triggers differ, one of the earliest pathophysiological changes observed in the liver is steatosis. The likelihood of some shared pathogenic mechanisms in NAFLD and ALD means that it may be possible to develop markers for prognostication or staging, or new therapeutic tools to treat both conditions. One such example of an approach exists in the form of the NACHT-, LRR-, and Livers 2021, 1, 68–81. We begin by providing an outline of the pathogenesis of alcohol and non-alcohol-related metabolic liver injury

The Pathogenesis of NAFLD

The Pathogenesis of Alcohol Related Liver Disease

The NLRP3 Inflammasome

Schematic representation of the canonical

This triggers the activation of caspase

Can Targeting of the NLRP3 Inflammasome Be of Benefit in Human Disease?