Xiao_2022_Int.Immunopharmacol_108_108741

BACKGROUND & AIMS: Hyperlipidemia is a lipid metabolism disorder associated with elevated serum triglyceride (TG) and/or cholesterol. Over the years, studies have shown that hyperlipidemia is associated with combordities, incluing diabetes and obesity, gradually becoming a public health concern. Current treatment approaches remain limited due to the lack of effective drugs. Here we investigated the function of recombinant humanized IgG1 in maintaining liver TG homeostasis and the underlying mechanisms. METHODS: ApoE(-/-) mice were fed a high-fat diet (HFD) for 20 weeks to induce hyperlipidemia. RNA sequencing (RNA-Seq) was performed to identify differences in gene expression in different groups of ApoE(-/-) mice liver. In vitro lipid accumulation in primary mouse hepatocytes was induced using a free fatty acid (FFA) mixture. Gene and protein expression were assessed in primary mouse hepatocytes by qPCR and Western blot. Gene reporter assays and ChIP-PCR were used to determine arylacetamide deacetylase (Aadac) promoter activity. RESULTS: Recombinant humanized IgG1 could significantly decrease the serum level of TG and low-density lipoproteins (LDL-C). Moreover, hepatic TG and lipid droplets were also reduced compared to the HFD group. Mouse liver RNA-Seq revealed that administration of recombinant humanized IgG1 significantly elevated the expression of Aadac. In vitro, knock-down of Aadac could nullify the effect of recombinant humanized IgG1 on decreasing the lipid droplets induced by FFA in primary mouse hepatocytes. Gene Reporter assays and ChIP-PCR demonstrated that the foxa1 response element in the Aadac promoter played a key role in Aadac expression induced by recombinant humanized IgG1. Moreover, recombinant humanized IgG1 repressed phosphorylation of PKCdelta and resulted in foxa1 elevation. Finally, neonatal Fc receptor (FcRn) knock-down reversed the effect of recombinant humanized IgG1 on the expression of PKCdelta phosphorylation, foxa1 and Aadac. CONCLUSIONS: Our findings suggest that recombinant humanized IgG1 plays an important role in maintaining liver TG homeostasis via the FcRn/PKCdelta/foxa1/Aadac pathway.