Abstract
Alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) are among the most frequent causes of chronic liver disease in the United States. Although the two entities are triggered by different etiologies — chronic alcohol consumption (ASH) and obesity-associated lipotoxicity (NASH) — they share overlapping histological and clinical features owing to common pathogenic mechanisms. These pathogenic processes include altered hepatocyte lipid metabolism, organelle dysfunction (i.e., ER stress), hepatocyte apoptosis, innate immune system activation, and hepatic stellate cell activation. Nonetheless, there are several disease-specific molecular signaling pathways, such as differential pathway activation downstream of TLR4 (MyD88-dependence in NASH versus MyD88-independence in ASH), inflammasome activation and IL-1β signaling in ASH, insulin resistance and lipotoxicity in NASH, and dysregulation of different microRNAs, which clearly highlight that ASH and NASH are two distinct biological entities. Both pathogenic similarities and differences have therapeutic implications. In this Review, we discuss these pathogenic mechanisms and their therapeutic implications for each disease, focusing on both shared and distinct targets.
Authors
Thomas Greuter, Harmeet Malhi, Gregory J. Gores, Vijay H. Shah
Figure 1
Pathogenic processes in alcoholic liver disease.
Ethanol leads to increased gut permeability, which results in an increased release of LPS into circulation. LPS then activates TLR4 on macrophages and hepatocytes to trigger inflammatory responses. Ethanol can also directly act on hepatocytes by inducing organelle dysfunction and oxidative stress, which result in induction of proapoptotic cascades. Hepatic cells release extracellular vesicles and damage-associated molecular patterns (DAMPs) that recruit macrophages to the site of cell death, resulting in hepatic stellate cell (HSC) activation and migration. Cell death receptors that incite apoptosis can be activated by TRAIL or via proinflammatory cytokines released from macrophages. SEC, sinusoidal endothelial cell. Illustrated by Mao Miyamoto.
