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Hyodeoxycholic acid ameliorates nonalcoholic fatty liver disease by inhibiting RAN-mediated PPARα nucleus-cytoplasm shuttling.

ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is usually characterized with disrupted bile acid (BA) homeostasis. However, the exact role of certain BA in NAFLD is poorly understood. Here we show levels of serum hyodeoxycholic acid (HDCA) decrease in both NAFLD patients and mice, as well as in liver and intestinal contents of NAFLD mice compared to their healthy counterparts. Serum HDCA is also inversely correlated with NAFLD severity. Dietary HDCA supplementation ameliorates diet-induced NAFLD in male wild type mice by activating fatty acid oxidation in hepatic peroxisome proliferator-activated receptor α (PPARα)-dependent way because the anti-NAFLD effect of HDCA is abolished in hepatocyte-specific Pparα knockout mice. Mechanistically, HDCA facilitates nuclear localization of PPARα by directly interacting with RAN protein. This interaction disrupts the formation of RAN/CRM1/PPARα nucleus-cytoplasm shuttling heterotrimer. Our results demonstrate the therapeutic potential of HDCA for NAFLD and provide new insights of BAs on regulating fatty acid metabolism.

SUBMITTER: Zhong J

PROVIDER: S-EPMC10482907 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Hyodeoxycholic acid ameliorates nonalcoholic fatty liver disease by inhibiting RAN-mediated PPARα nucleus-cytoplasm shuttling.

Zhong Jing J He Xiaofang X Gao Xinxin X Liu Qiaohong Q Zhao Yu Y Hong Ying Y Zhu Weize W Yan Juan J Li Yifan Y Li Yan Y Zheng Ningning N Bao Yiyang Y Wang Hao H Ma Junli J Huang Wenjin W Liu Zekun Z Lyu Yuanzhi Y Ke Xisong X Jia Wei W Xie Cen C Hu Yiyang Y Sheng Lili L Li Houkai H

Nature communications 20230906 1

Nonalcoholic fatty liver disease (NAFLD) is usually characterized with disrupted bile acid (BA) homeostasis. However, the exact role of certain BA in NAFLD is poorly understood. Here we show levels of serum hyodeoxycholic acid (HDCA) decrease in both NAFLD patients and mice, as well as in liver and intestinal contents of NAFLD mice compared to their healthy counterparts. Serum HDCA is also inversely correlated with NAFLD severity. Dietary HDCA supplementation ameliorates diet-induced NAFLD in ma ...[more]

PMID: 37673856

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Project description:BackgroundIn-depth exploration into the dysregulation of lipid metabolism in hepatocellular carcinoma (HCC) has contributed to the development of advanced antitumor strategies. CRSP8 is a critical component of mediator multiprotein complex involved in transcriptional recruiting. However, the regulatory mechanisms of CRSP8 on fatty acid metabolism reprogramming and HCC progression remain unclear.MethodsIn-silico/house dataset analysis, lipid droplets (LDs) formation, HCC mouse models and targeted lipidomic analysis were performed to determine the function of CRSP8 on regulating lipid metabolism in HCC. The subcellular colocalization and live cell imaging of LDs, transmission electron microscopy, co-immunoprecipitation and luciferase reporter assay were employed to investigate their potential mechanism.ResultsCRSP8 was identified as a highly expressed oncogene essential for the proliferation and aggressiveness of HCC in vitro and in vivo. The tumor promotion of CRSP8 was accompanied by LDs accumulation and increased de novo fatty acids (FAs) synthesis. Moreover, CRSP8 diminished the colocalization between LC3 and LDs to impair lipophagy in a nuclear-localized PPARα-dependent manner, which decreased the mobilization of FAs from LDs degradation and hindered mitochondrial fatty acid oxidation. Mechanistically, the small ras family GTPase RAN was transcriptionally activated by CRSP8, leading to the reinforcement of RAN/CRM1-mediated nuclear export. CRSP8-induced enhanced formation of RAN/CRM1/PPARα nucleus-cytoplasm shuttling heterotrimer orchestrated cytoplasmic translocation of PPARα, attenuated nPPARα-mediated lipophagy and fatty acid catabolism, subsequently exacerbated HCC progression. In CRSP8-enriched HCC, lipid synthesis inhibitor Orlistat effectively reshaped the immunosuppressive tumor microenvironment (TME) and improved the efficacy of anti-PD-L1 therapy in vivo.ConclusionOur study establishes that CRSP8-driven fatty acid metabolism reprogramming facilitates HCC progression via the RAN/CRM1/PPARα nucleus-cytoplasm shuttling heterotrimer and impaired lipophagy-derived catabolism. Targeting the energy supply sourced from lipids could represent a promising therapeutic strategy for treating CRSP8-sufficient HCC.

Project description:Statins, the intestinal cholesterol transporter inhibitor (ezetimibe), and PCSK9 inhibitors can reduce serum LDL-C levels, leading to a significant reduction in cardiovascular events. However, these events cannot be fully prevented even when maintaining very low LDL-C levels. Hypertriglyceridemia and reduced HDL-C are known as residual risk factors for ASCVD. Hypertriglyceridemia and/or low HDL-C can be treated with fibrates, nicotinic acids, and n-3 polyunsaturated fatty acids. Fibrates were demonstrated to be PPARα agonists and can markedly lower serum TG levels, yet were reported to cause some adverse effects, including an increase in the liver enzyme and creatinine levels. Recent megatrials of fibrates have shown negative findings on the prevention of ASCVD, which were supposed to be due to their low selectivity and potency for binding to PPAR α. To overcome the off-target effects of fibrates, the concept of a selective PPARα modulator (SPPARMα) was proposed. Kowa Company, Ltd. (Tokyo, Japan), has developed pemafibrate (K-877). Compared with fenofibrate, pemafibrate showed more favorable effects on the reduction of TG and an increase in HDL-C. Fibrates worsened liver and kidney function test values, although pemafibrate showed a favorable effect on liver function test values and little effect on serum creatinine levels and eGFR. Minimal drug-drug interactions of pemafibrate with statins were observed. While most of the fibrates are mainly excreted from the kidney, pemafibrate is metabolized in the liver and excreted into the bile. It can be used safely even in patients with CKD, without a significant increase in blood concentration. In the megatrial of pemafibrate, PROMINENT, for dyslipidemic patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL-C and LDL-C levels, the incidence of cardiovascular events did not decrease among those receiving pemafibrate compared to those receiving the placebo; however, the incidence of nonalcoholic fatty liver disease was lower. Pemafibrate may be superior to conventional fibrates and applicable to CKD patients. This current review summarizes the recent findings on pemafibrate.

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Hyodeoxycholic acid ameliorates nonalcoholic fatty liver disease by inhibiting RAN-mediated PPARα nucleus-cytoplasm shuttling.

Publications

Hyodeoxycholic acid ameliorates nonalcoholic fatty liver disease by inhibiting RAN-mediated PPARα nucleus-cytoplasm shuttling.

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