Diabetes, Metabolic Syndrome and Obesity (Mar 2020)
Loss of HNF1α Function Contributes to Hepatocyte Proliferation and Abnormal Cholesterol Metabolism via Downregulating miR-122: A Novel Mechanism of MODY3
Abstract
Mengdie Hu, Xiuting Huang, Xueyao Han, Linong Ji Department of Endocrinology and Metabolism, Peking University People’s Hospital, Peking University Diabetes Center, Beijing 100044, People’s Republic of ChinaCorrespondence: Linong Ji; Xueyao HanDepartment of Endocrinology and Metabolism, Peking University People’s Hospital, Peking University Diabetes Center, Beijing 100044, People’s Republic of ChinaTel +86 10-8832 5578Fax +86 10-8832 4371Email [email protected]; [email protected]: Mutations in hepatocyte nuclear factor 1α (HNF1α) are the cause of maturity-onset diabetes of the young type 3 (MODY3) and involved in the development of hepatocellular adenoma and abnormal lipid metabolism. Previously, we have found that the serum microRNA (miR)-122 levels in MODY3 patients were lower than those in type 2 diabetes mellitus and healthy controls. This study aimed to investigate the mechanism of decreased miR-122 levels in patients with MODY3 and whether low levels of miR-122 mediate tumorigenesis and abnormal lipid metabolism associated with HNF1α deficiency in human hepatocytes.Methods: The expression of miR-122 was examined by real-time PCR. Dual-luciferase reporter assay was performed to confirm the transcriptional regulation of miR-122 by HNF1α. HepG2 cells were transfected with siRNA or miRNA mimic to downregulate or upregulate the expression of HNF1α or miR-122, respectively. CCK-8 and colony formation assay were used to determine cell proliferation. Lipid accumulation was examined by Oil Red O staining and intracellular triglyceride and cholesterol quantification assays.Results: HNF1α regulated the expression of miR-122 by directly binding to its promoter. Knockdown of HNF1α in HepG2 cells reduced the expression of miR-122, increased proliferation and promoted intracellular cholesterol accumulation. Overexpression of miR-122 partially rescued the phenotypes associated with HNF1α deficiency in human hepatocytes. Mechanistically, HNF1α modulated cholesterol homeostasis via miR-122-dependent activation of sterol regulatory element-binding protein-2 (SREBP-2) and regulation of proprotein convertase subtilisin/kexin type 9 (PCSK9). Moreover, circulating miR-122 levels were associated with serum cholesterol levels.Conclusion: Loss of HNF1α function led to hepatocyte proliferation and abnormal cholesterol metabolism by downregulating miR-122. Our findings revealed a novel mechanism that low levels of miR-122 mediate tumorigenesis and abnormal lipid metabolism associated with MODY3. MiR-122 may be a potential therapeutic target for the treatment of MODY3.Keywords: MODY3, HNF1α, miR-122, cholesterol metabolism, hepatocellular adenoma
