Function and therapeutic advances of chemokine and its receptor in nonalcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of hepatic pathology, ranging from simple accumulation of fat in its most benign form, steatohepatitis, to cirrhosis in its most advanced form. The prevalence of NAFLD is 20-30% in adults, and 10-20% of patients with NAFLD progress to nonalcoholic steatohepatitis (NASH) which is predicted to be the leading cause of liver transplantation over the next 10 years. Therefore, it is essential to explore effective diagnostic and treatment strategies for NAFLD patients. Chemokines are a family of small and highly conserved proteins (molecular weight ranging from 8 to 12 kDa) involved in regulating the migration and activities of hepatocytes, Kupffer cells (KCs), hepatic stellate cells (HSCs), endothelial cells and circulating immune cells. Accumulating data show that chemokine and its receptor act vital roles in the pathogenesis of NAFLD. Herein, we summarize the involvement of the chemokine and its receptor in the pathogenesis of NAFLD and explore the novel pharmacotherapeutic avenues for patients with NAFLD.

Keywords: NAFLD; chemokine; chemokine receptor; hepatocellular carcinoma; steatohepatitis.

Figure 1.

The ‘multiple hit’ hypothesis for the progression of NAFLD and natural history of NAFLD: dietary habits, environmental and genetic factors result in the development of insulin resistance, obesity with adipocyte proliferation and changes in the gut microbiome. Insulin resistance leads to increased hepatic DNL and dysfunction of adipose tissue and adipocyte. Fat accumulates in the liver in the form of TG. Contemporarily, this happens with increased lipotoxicity from high levels of FFAs, free CH and other lipid metabolites, which induce mitochondrial dysfunction with oxidative stress and production of ROS and ER stress with activation of UPR. All these factors lead to hepatic inflammation, apoptosis and fibrosis. Also, the altered gut microbiome results in more production of FFAs and CH and increases small bowel permeability. Increased fatty acid absorption causes the activation of inflammasome such as LPS, and the release of proinflammatory cytokines such as IL-6 and TNF-α. CH, cholesterol; DNL, de novo lipogenesis; ER, endoplasmic reticulum; FFA, free fatty acid; HCC, hepatocellular carcinoma; IL, interleukin; LPS, lipopolysaccharide; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; ROS, reactive oxygen species; TG, triglyceride; TNF-α, tumor necrosis factor alpha; UPR, unfolded protein response; VLDL, very low density lipoprotein.

Figure 2.

The structure of chemokines. The structures of chemokines are similar with at least three β-pleated sheets (indicated as β1-3) and a C-terminal a-helix. In the CXC chemokine family, the two cysteines nearest the N-termini are separated by a single and variable amino acid. In the CC chemokine family, the two cysteines nearest the N-termini are adjacent. In the C chemokine family, only one cysteine is near its N-terminus. The CX3C chemokine has a typical chemokine-like structure. The two cysteines nearest the N-termini are separated by three amino acids. In addition, the chemokine domain occurs at the end of a long stalk which is largely replaced by mucin-like carbohydrates. The protein is fixed in the membrane and has a short cytoplasmic domain.

Figure 3.

The structure of the typical chemokine receptor. Chemokine receptors are embedded in the lipid bilayer of the cell surface and possess seven transmembrane domains.