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  • Title: The metabolic regulator small heterodimer partner contributes to the glucose and lipid homeostasis abnormalities induced by hepatitis C virus infection.
    Author: Chen J, Zhou Y, Zhuang Y, Qin T, Guo M, Jiang J, Niu J, Li JZ, Chen X, Wang Q.
    Journal: Metabolism; 2019 Nov; 100():153954. PubMed ID: 31400386.
    Abstract:
    BACKGROUND: Chronic hepatitis C virus (HCV) infection can predispose the host to metabolic abnormalities. The orphan nuclear receptor small heterodimer partner (SHP; NR0B2) has been identified as a key transcriptional regulatory factor of genes involved in diverse metabolic pathways. The protective effects of SHP against HCV-induced hepatic fibrosis have been reported. However, the exact mechanisms of its role on metabolism are largely unknown. We investigated the role of hepatic SHP in regulating glucose and lipid homeostasis, particularly in the metabolic stress response caused by HCV infection. MATERIALS AND METHODS: Gluconeogenesis and lipogenesis levels and SHP expression were measured in HCV-infected cells, as well as in liver samples from HCV-infected patients and persistently HCV-infected mice. RESULTS: We demonstrated that SHP is involved in gluconeogenesis via the acetylation of the Forkhead box O (FoxO) family transcription factor FoxO1, which is mediated by histone deacetylase 9 (HDAC9). Meanwhile, SHP regulates lipogenesis in the liver via suppressing the induction of sterol regulatory element-binding protein-1c (SREBP-1c) expression by the SUMOylation of Liver X receptor α (LXRα) at the SREBP-1c promoter. In particular, SHP can be strongly reduced upon stimulation, such as by HCV infection. The SHP expression levels were decreased in the livers from the CHC patients and persistently HCV-infected mice, and a negative correlation was observed between the SHP expression levels and gluconeogenic or lipogenic activities, emphasizing the clinical relevance of these results. CONCLUSIONS: Our results suggest that SHP is involved in HCV-induced abnormal glucose and lipid homeostasis and that SHP could be a major target for therapeutic interventions targeting HCV-associated metabolic diseases.
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