Transcriptional control by HNF-1: Emerging evidence showing its role in lipid metabolism and lipid metabolism disorders

Abstract

The present review focuses on the roles and underlying mechanisms of action of hepatic nuclear factor-1 (HNF-1) in lipid metabolism and the development of lipid metabolism disorders. HNF-1 is a transcriptional regulator that can form homodimers, and the HNF-1α and HNF-1β isomers can form heterodimers. Both homo- and heterodimers recognize and bind to specific cis-acting elements in gene promoters to transactivate transcription and to coordinate the expression of target lipid-related genes, thereby influencing the homeostasis of lipid metabolism. HNF-1 was shown to restrain lipid anabolism, including synthesis, absorption, and storage, by inhibiting the expression of lipogenesis-related genes, such as peroxisome proliferator-activated receptor γ (PPARγ) and sterol regulatory element-binding protein-1/2 (SREBP-1/2). Moreover, HNF-1 enhances the expression of various genes, such as proprotein convertase subtilisin/kexin type 9 (PCSK9), glutathione peroxidase 1 (GPx1), and suppressor of cytokine signaling-3 (SOCS-3) and negatively regulates signal transducer and activator of transcription (STAT) to facilitate lipid catabolism in hepatocytes. HNF-1 reduces hepatocellular lipid decomposition, which alleviates the progression of nonalcoholic fatty liver disease (NAFLD). HNF-1 impairs preadipocyte differentiation to reduce the number of adipocytes, stunting the development of obesity. Furthermore, HNF-1 reduces free cholesterol levels in the plasma to inhibit aortic lipid deposition and lipid plaque formation, relieving dyslipidemia and preventing the development of atherosclerotic cardiovascular disease (ASCVD). In summary, HNF-1 transcriptionally regulates lipid-related genes to manipulate intracorporeal balance of lipid metabolism and to suppress the development of lipid metabolism disorders.