CXC Motif Ligand 16 Promotes Nonalcoholic Fatty Liver Disease Progression via Hepatocyte-Stellate Cell Crosstalk

Context: Nonalcoholic fatty liver disease (NAFLD) is a focus of attention because of its prevalence. CXC motif ligand 16 (CXCL16) has been studied in inflammatory and metabolic diseases. Objective: To investigate the role of CXCL16 in steatosis and fibrosis in patients with NAFLD. Design: Liver specimens and sera of patients with NAFLD were collected from 2012 to 2017. Setting: Beijing 302 Hospital. Participants: 117 patients with NAFLD and 15 healthy controls. Interventions: None. Main Outcome Measures: The main outcome measures were CXCL16 levels in sera and biopsy specimens of patients with NAFLD. Results: CXCL16 serum level was markedly elevated in patients with NAFLD, especially in those at the S3 steatosis level according to the steatosis, activity, and fibrosis (SAF) scoring system. The different serum levels of CXCL16 between groups were due to data in patients with A or F scores >= 2, according to the SAF scoring system. CXCL16 accumulated around steatotic hepatocytes in biopsy specimens. In vitro, CXCL16 treatment led to severe steatosis of hepatocytes in the hepatocytestellate cell coculture system and suppressed the respiration rate of hepatocytes. Lipogenic gene expression and hepatic stellate cell activation indexes were increased in a CXCL16 overexpression system. In addition, ligands in the Hedgehog pathway cascade were downregulated in hepatocytes. Conclusions: CXCL16 was highly expressed in patients with NAFLD, suggesting that it may contribute to steatotic and fibrotic progression. CXCL16 may be a potential noninvasive marker of NAFLD and a future potential therapeutic target to treat NAFLD.