Immunological mechanisms and therapeutic targets of fatty liver diseases

Abstract

Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are the two major types of chronic liver disease worldwide. Inflammatory processes play key roles in the pathogeneses of fatty liver diseases, and continuous inflammation promotes the progression of alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH). Although both ALD and NAFLD are closely related to inflammation, their respective developmental mechanisms differ to some extent. Here, we review the roles of multiple immunological mechanisms and therapeutic targets related to the inflammation associated with fatty liver diseases and the differences in the progression of ASH and NASH. Multiple cell types in the liver, including macrophages, neutrophils, other immune cell types and hepatocytes, are involved in fatty liver disease inflammation. In addition, microRNAs (miRNAs), extracellular vesicles (EVs), and complement also contribute to the inflammatory process, as does intertissue crosstalk between the liver and the intestine, adipose tissue, and the nervous system. We point out that inflammation also plays important roles in promoting liver repair and controlling bacterial infections. Understanding the complex regulatory process of disrupted homeostasis during the development of fatty liver diseases may lead to the development of improved targeted therapeutic intervention strategies.

Keywords: ALD; NAFLD; cytokine; immune; inflammation; target.

Fig. 1

Triggers of the immune response in ALD. Dysregulated intestinal barrier integrity and gut microbiota products/metabolites play important roles in modulating ALD. The gut communicates with the liver via the gut–liver axis through the biliary system and the portal vein, transferring gut-derived components or the gut microbiota themselves to the liver and initiating the immune response. Chronic alcohol consumption disrupts the gut barrier, leading to increased gut permeability and ectopic immune stimulation. Chronic alcohol ingestion decreases intestinal REG3G expression, which is negatively associated with the number of mucosa-associated bacteria in both human patients and experimental mouse models. Alcohol exposure causes loss of epithelial cells at the tips of intestinal villi and a reduction in the levels of tight junction proteins. Adipose-liver organ crosstalk is mediated by the release of mediators, including neurotransmitters, cytokines, chemokines, adipocytokines, miRNAs, EVs, and metabolites, and the crosstalk between the liver and adipose tissue participates in promoting liver inflammation and injury in ALD. These mediators further activate immune cells, which release proinflammatory cytokines and chemokines, causing hepatocyte death

Fig. 2

Triggers of the immune response in NAFLD. The gut microbiota plays a key role in the pathogenesis of NAFLD. Gut barrier dysfunction increases bacterial translocation and promotes NAFLD progression. The destruction of the intestinal vascular barrier by the microbiota causes bacteria or bacterial products to enter the blood circulation, which is a prerequisite for liver inflammation and the development of NASH. Crosstalk between adipose tissue and the liver affects systemic metabolism and insulin resistance. Adipose tissue plays a key role in regulating NASH development by secreting adiponectin, leptin, TNF, and IL-6. In addition, some lipid moieties (palmitic acid, ceramide) released by adipocytes also hinder the function of the ER and mitochondria, causing cell stress and even hepatocyte death. Hepatocyte death is one of the key triggers of liver inflammation in NAFLD and NASH progression. In addition, KCs produce TNF, TRAIL, and FAS ligands through phagocytosis of apoptotic bodies, which subsequently promotes hepatocyte apoptosis and causes hepatitis and fibrosis. The release of IL-1β and IL-18 into the circulation activates the immune system, and the alteration of autophagy in hepatocytes and nonparenchymal cells (KCs and HSCs) contributes to NASH pathogenesis