Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily. It forms a heterodimer with the retinoid X receptor (RXR) and binds to the consensus DNA-binding sequence in the regulatory region of the target genes (Tontonoz and Spiegelman, 2008). Although PPARγ expression is the highest in adipose tissue, its expression is markedly increased in the liver of patients with non-alcoholic fatty liver disease (NAFLD) and NAFLD model mice, such as leptin-deficient (ob/ob) mice (Anstee and Goldin, 2006; Pettinelli and Videla, 2011; Rahimian et al., 2001). Ob/ob mice are a well-known type 2 diabetes model characterized by obesity, hyperinsulinemia, hyperglycemia, and severe liver steatosis (Suriano et al., 2021).

Since Pparg-null mice are non-viable (Barak et al., 1999), liver-specific Pparg knockout (PPARγLKO) mice were generated by crossing mice expressing Cre recombinase regulated by the albumin promoter with Pparg-floxed mice (Matsusue et al., 2003). To investigate the role of PPARγ in hepatic lipid metabolism and type 2 diabetes, PPARγLKO mice were crossed with ob/ob mice to generate ob/ob-PPARγLKO mice. Ob/ob-PPARγLKO mice exhibit significantly lower hepatic triglyceride (TG) levels (Matsusue et al., 2003), suggesting that PPARγ is essential for TG accumulation in hepatocytes and promotes the development of fatty liver.

Using subtractive cDNA cloning strategy, a previous study showed that fat-specific protein 27 (Fsp27) is highly expressed in the fatty liver but not in the normal mouse liver. Fsp27, a PPARγ-target gene, promotes lipid accumulation in the liver (Matsusue et al., 2008). Fsp27 has two isoforms, Fsp27a (mouse)/CIDEC1 (human) and Fsp27b (mouse)/CIDEC2 (human) (Xu et al., 2015), both of which are direct PPARγ-target genes (Aibara et al., 2020a, Aibara et al., 2020b; Matsusue et al., 2008). These studies indicate that high expression of PPARγ-target genes contributes to hepatic fat accumulation.

Human and mouse oxysterol-binding protein-like 3 (OSBPL3) belongs to the oxysterol-binding protein (OSBP) family, which consists of 12 members (OSBP, OSBPL1-OSBPL11) (Anniss et al., 2002). OSBP family proteins are intracellular lipid-binding/transport proteins that are necessary for lipid transport and maintenance of cholesterol balance in the body (Olkkonen, 2015). It has been reported that OSBPL3 is highly expressed in the liver of SUMOylation-defective liver receptor homolog 1 (LRH-1) mutant mice (LRH-1 K289R mice) (Stein et al., 2017). Furthermore, OSBPL3 enhances sterol regulatory element-binding protein 1 (SREBP1) processing and promotes fat accumulation in the liver by activating de novo lipogenesis (Stein et al., 2017). These studies suggest that OSBPL3 plays a key role in hepatic fat accumulation.

In our previous study, we analyzed the global gene expression profile of the fatty liver from patients with advanced NAFLD and ob/ob mice using microarrays and found that Osbpl3 is strongly expressed in the fatty liver. Furthermore, we observed that liver-specific PPARγ deficiency reduced the expression of Osbpl3 in the fatty liver of ob/ob mice. In this study, we investigated the mechanism by which PPARγ regulates OSBPL3 expression in the fatty liver.