Nonalcoholic fatty liver disease (NAFLD), the most prevalent liver disease, is characterized by lipid deposition and steatosis in hepatocytes. NAFLD is not caused by alcohol or other liver injury-inducing factors such as drugs and viruses [1], [2]. NAFLD is a continuum of fatty liver diseases ranging from steatosis with or without mild inflammation to nonalcoholic steatohepatitis (NASH), which is characterized by necrotizing inflammation and often progresses to fibrosis [3]. Under certain circumstances, NAFLD may develop into more serious diseases such as hepatocellular carcinoma, cirrhosis, and fibrosis [4]. Although an increasing number of studies have shown that NAFLD is strongly associated with obesity, insulin resistance, dyslipidemia, hypertension and metabolic syndrome, its specific pathogenesis remains unclear [5], [6].

Chemokines (C-X-C motif) have been shown to regulate angiogenesis, fibrosis, proliferation, cytotoxicity and apoptosis in addition to attracting inflammatory cell aggregates [7]. Chemokine ligand 6 (CXCL6, also called granulocyte chemotactic protein 2) is a key member of the CXC chemokine family. By binding to the chemokine receptors CXCR2 and CXCR1, CXCL6 mediates the recruitment of inflammatory cells to areas of inflammation [8]. Both CXCR1 and CXCR2 have been shown to participate in liver repair and regeneration [9], [10], while Cai et al. found that CXCL6 was involved in liver fibrosis through stimulating the release of TGF‐β by Kupffer cells [11]. In addition, a recent study demonstrated that CXCL6 was overexpressed in hepatocyte and mouse models of early alcoholic liver disease [12]. However, the effects of CXCL6 on NAFLD remain undefined.

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear receptor superfamily. There are three distinct PPAR isoforms, PPARγ, PPARδ and PPARα, that exhibit diverse tissue expression profiles and a range of functions [13]. Early studies have confirmed that PPARα controls the expression of multiple genes that are involved in almost every aspect of lipid metabolism, including ketogenesis, peroxisomal and mitochondrial fatty acid oxidation, fatty acid uptake, as well as the generation and breakdown of lipid droplets and triglycerides [14]. PPARα has a significant impact on lipid metabolism, and its impairment can trigger the inflammation and fibrosis associated with NAFLD [15]. A correlation between the activation of PPARα and CXCL6 has previously been shown in human liver tissue sections [16]. However, the correlation between PPARα and CXCL6 in NAFLD remains elusive.

In the current study, we examined CXCL6 levels in the serum of NAFLD patients and sought to determine the role of CXCL6 in the pathogenesis of NAFLD. Our findings reveal that CXCL6 promotes the progression of NAFLD through PPARα, as well as identify novel targets that will be beneficial in the development of new therapeutic strategies.