Hepatic G Protein-Coupled Receptor 180 Deficiency Ameliorates High Fat Diet-Induced Lipid Accumulation via the Gi-PKA-SREBP Pathway.

Single-nucleotide polymorphisms in G protein-coupled receptor 180 (GPR180) are associated with hypertriglyceridemia. The aim of this study was to determine whether hepatic GPR180 impacts lipid metabolism. Hepatic GPR180 was knocked down using two approaches: -specific short hairpin (sh)RNA carried by adeno-associated virus 9 (AAV9) and transgene established by crossbreeding mice with animals, in which Gpr180 was specifically knocked down in hepatocytes. Adiposity, hepatic lipid contents, and proteins related to lipid metabolism were analyzed. The effects of GPR180 on triglyceride and cholesterol synthesis were further verified by knocking down or overexpressing in Hepa1-6 cells. mRNA was upregulated in the liver of HFD-induced obese mice. Deficiency of decreased triglyceride and cholesterol contents in the liver and plasma, ameliorated hepatic lipid deposition in HFD-induced obese mice, increased energy metabolism, and reduced adiposity. These alterations were associated with downregulation of transcription factors SREBP1 and SREBP2, and their target acetyl-CoA carboxylase. In Hepa1-6 cells, knockdown decreased intracellular triglyceride and cholesterol contents, whereas its overexpression increased their levels. Overexpression of significantly reduced the PKA-mediated phosphorylation of substrates and consequent CREB activity. Hence, GPR180 might represent a novel drug target for intervention of adiposity and liver steatosis.