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.

Keywords: ASCVD; HNF-1; Lipid metabolism; NAFLD; Obesity.

Figure 1

The structures of the HNF-1 protein. (A) A scheme of the structure of the HNF-1 protein. The polypeptide chain of human HNF-1 contains 631 amino acid residues, and the first 280 amino acid residues form an amino-terminal dimerization domain (aa 1-32), an extremely acidic area (aa 71-80), and a POU domain (aa 98-280). The carboxy-terminal domain (aa 281-631) is responsible for transcriptional activation by HNF-1 and contains three transactivation domains: activation domain I (ADI), including amino acids 546-628; ADII, including amino acids 281-318; and ADIII, including amino acids 440-506. (B) Three-dimensional structures of the HNF-1α homodimer. (C) Three-dimensional structures of the HNF-1β homodimer. , amino-terminus; , carboxy-terminus.

Figure 2

The regulatory roles and pathways of HNF-1 in hepatocellular lipid metabolism and NAFLD. Abbreviations: PCSK9, proprotein convertase subtilisin/kexin type 9; miR-122, microRNA-122; SREBP-1/2, sterol regulatory element-binding protein-1/2; SCAP, SREBP cleavage-activating protein; ACC, acetyl-CoA carboxylase; L-FABP, liver fatty acid-binding protein; HL, hepatic lipase; FAS, fatty acid synthetase; SOCS-3, suppressor of cytokine signaling-3; STAT3, signal transducer and activator of transcription 3; FFA, free fatty acid; DPP4, dipeptidyl peptidase 4; NOX1, nicotinamide adenine dinucleotide phosphate oxidase 1; Angptl8, angiopoietin-like 8; and NAFLD, nonalcoholic fatty liver disease. Solid lines indicate regulatory pathways known to be associated with NAFLD, and dotted lines indicate regulatory pathways with unconfirmed associations with NAFLD. →, promotion; −, inhibition.

Figure 3

The regulatory roles and pathways of HNF-1 in lipid metabolism in adipocytes and obesity. Abbreviations: PPARγ, peroxisome proliferator-activated receptor-γ; SigR1, sigma receptor 1; A1254, aroclor 1254-regulated processes. Solid lines indicate regulatory pathways known to be associated with obesity, and dotted lines indicate regulatory pathways with unconfirmed associations with obesity. →, promotion; −, inhibition.

Figure 4

The regulatory roles and pathways of HNF-1 in hepatic lipid metabolism and ASCVD. PPARγ, peroxisome proliferator-activated receptor γ; A1254, aroclor 1254-regulated processes; GPx1, glutathione peroxidase 1; DPP4, dipeptidyl peptidase 4; NOX1, nicotinamide adenine dinucleotide phosphate oxidase 1; L-FABP, liver fatty acid-binding protein; ACC, acetyl-CoA carboxylase; FAS, fatty acid synthetase; HL, hepatic lipase; LDL, low density lipoprotein; TG, triglyceride; VLDL, very low density lipoproteins; IDL, intermediate density lipoprotein; and ASCVD, atherosclerotic cardiovascular disease. Solid lines indicate regulatory pathways known to be associated with ASCVD, and dotted lines indicate regulatory pathways with unconfirmed associations with ASCVD. →, promotion; −, inhibition.