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Oridonin restores hepatic lipid homeostasis in an LXRa-ATGL/EPT1 axis-dependent manner

Journal of Pharmaceutical Analysis 2023年第11期13卷 1281-1295页

作者： Yulian Chen Huanguo Jiang Zhikun Zhan Jindi Lu Tanwei Gu Ping Yu Weimin Liang Xi Zhang Shilong Zhong Lan Tang NMPA Key Laboratory for Research and Evaluation of Drug Metabolism Guangdong Provincial Key Laboratory of New Drug ScreeningSchool of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou510515China Department of Pharmacy Guangdong Provincial People's Hospital(Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhou510515China

Hepatosteatosis is characterized by abnormal accumulation of triglycerides(TG),leading to prolonged and chronic inflammatory infiltration.To date,there is still a lack of effective and economical therapies for hepatosteatosis.Oridonin(ORI)is a major bioactive component extracted from the traditional Chinese medicinal herb Rabdosia rubescens.In this paper,we showed that ORI exerted significant protective effects against hepatic steatosis,inflammation and fibrosis,which was dependent on LXRa signaling.It is reported that LXRa regulated lipid homeostasis between triglyceride(TG)and phosphatidylethanolamine(PE)by promoting ATGL and EPT1 expression.Therefore,we implemented the lipidomic strategy and luciferase reporter assay to verify that ORI contributed to the homeostasis of lipids via the regulation of the ATGL gene associated with TG hydrolysis and the EPT1 gene related to PE synthesis in a LXRadependent manner,and the results showed the TG reduction and PE elevation.In detail,hepatic TG overload and lipotoxicity were reversed after ORI treatment by modulating the ATGL and EPT1 genes,respectively.Taken together,the data provide mechanistic insights to explain the bioactivity of ORI in attenuating TG accumulation and cytotoxicity and introduce exciting opportunities for developing novel natural activators of the LXRa-ATGL/EPT1 axis for pharmacologically treating hepatosteatosis and metabolic disorders.

关键词： Oridonin lipid homeostasis TG reduction PE elevation LXRa-ATGL/EPT1 axis

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Liver-specific Reduction of Mfn2 Protein by RNAi Results in Impaired Glycometabolism and lipid homeostasis in BALB/c Mice

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2009年第6期29卷 689-696页

作者：陈小琳徐焱成 Department of Endocrinology Renmin Hospital of Wuhan University Department of Endocrinology Zhongnan Hospital of Wuhan University

Mitofusin-2 （Mfn2） gene expression is positively correlated with insulin sensitivity in patients with type 2 diabetes. However, it is unclear if Mfn2 is involved in carbohydrate metabolism and lipid homeostasis. In order to investigate the specific functions of Mfn2 in glycometabolism and lipid homeostasis in BALB/c mice, a RNA interference technique-mediated hydrodynamic injection was developed, in which short hairpin RNAs （shRNAs） were used to inhibit the Mfn2 expression in vivo. Seventy-two mice were randomly divided into two groups： the Mfn2 reduction group （Mfn2/shRNA） and the negative control group （NC）. Intraperitoneal glucose tolerance tests and intraperitoneal insulin tolerance tests were used to evaluate glycometabolism and insulin sensitivity. D-（3-3H） glucose or 3H2O was injected into the tail vein or intraperitoneally to facilitate the calculation of the rate of hepatic glucose production and fatty acid synthesis in vivo. The results showed that, in Mfn2/shRNA mice, the liver Mfn2 protein was significantly decreased, and fasting blood glucose concentrations were increased by approximately 48%, when compared with the NC mice. In parallel with the changes in fasting glucose levels, hepatic glucose production was significantly elevated in Mfn2/shRNA mice. When insulin was administrated, these mice exhibited impaired insulin tolerance. It was also found that the reduction of Mfn2 markedly decreased the rate of fatty acid synthesis in the liver, and the Mfn2/shRNA mice exhibited hypertriglyceridema. Taken together, our results indicate that Mfn2 plays an important role in maintaining glucose and lipid homeostasis, and in the development of insulin resistance in vivo.

关键词： Mitofusin-2 RNA interference glycometabolism lipid homeostasis

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Nuclear transcription factors and lipid homeostasis in liver

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Chinese Medical Journal 2007年第24期120卷 2290-2296页

作者： CHEN Ya-xi HUANG Ai-long RUAN Xiong-zhong Centre for lipid Research,Key Laboratory of Molecular Biology on Infectious Diseases,Ministry of Education Second Affiliated Hospital,Chongqing Medical University,Chongqing 400010,China(Chen YX,Huang AL and Ruan XZ) Centre for lipid Research Key Laboratory of Molecular Biology on Infectious DiseasesMinistry of Education

The liver plays a major role in the regulation , glucose, lipid and energy metabolism. Increasd hepatic fat deposit is a very common feature in obese, insulin-resistant patients, in metabolic syndrome, alcoholic steatohepatitis （ASH） and nonalchoholic fatty liver disaseas （NAFLD）. As a central organ for whole body lipid metabolism, disruption of the normal mechanisms for synthesis, transport and removal/ metabolism of long-chain fatty acids and triglycerides are the basis for the development of fatty liver. The exact mechanisms that link hepatic lipid accumulation, impaired glucose metabolism, and insulin resistance are unknown, but increasing evidence suggest that nuclear transcription factors play important roles. Members of the nuclear receptor superfamily, especially the peroxisome proliferator-activated receptors （PPARs） and the liver X receptor （LXR）, other factors such as sterol regulatory element binding proteins （SREBPs）, carbohydrate- response element-binding protein （ChREBP）, and nuclear transcription fator-κB （NF-κB） have emerged as dominant regulators of these processes, but the relative role of each of these factors in fatty liver disease is still undefined.

关键词： nuclear transcription factors lipid homeostasis fatty liver

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The molecular pathogenic role of inflammatory stress in dysregulation of lipid homeostasis and hepatic steatosis

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Genes & Diseases 2014年第1期1卷 106-112页

作者： Yaxi Chen Zac Varghese Xiong Z.Ruan Centre for lipid Research Key Laboratory of Molecular Biology on Infectious DiseasesMinistry of EducationChongqing Medical UniversityChongqingChina John Moorhead Research Laboratory Centre for NephrologyUniversity College London Medical SchoolRoyal Free CampusLondonUK

Non-alcoholic Fatty Liver Disease(NAFLD)is becoming the leading cause of chronic liver injury in developed countries and China.Chronic systemic inflammation plays a decisive role and is fundamental in the progression of NAFLD from simple steatosis(SS)toward higher risk nonalcoholic steatohepatitis(NASH)states.However,the exact mechanisms by which inflammation leading to NASH are incompletely understood.In this review,we focus the role of the cross talk between inflammation and lipid homeostasis on the progression of NAFLD.

关键词： Ectopic lipid deposition Inflammation lipid homeostasis lipid redistribution Non-alcoholic fatty liver disease

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The LXRB-SREBP1 network regulates lipogenic homeostasis by controlling the synthesis of polyunsaturated fatty acids in goat mammary epithelial cells

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Journal of Animal Science and Biotechnology 2023年第2期14卷 614-626页

作者： Wenying Zhang Changhui Zhang Jun Luo Huifen Xu Jianxin Liu Juan JLoor Hengbo Shi Institute of Dairy Science College of Animal SciencesZhejiang UniversityHangzhou 310058China College of Animal Science and Technology Northwest A&F UniversityYangling 712100China College of Animal Science and Technology Henan Agricultural UniversityZhengzhou 450046China Key Laboratory of Molecular Animal Nutrition(Zhejiang University) Ministry of EducationHangzhou310058China Mammalian Nutrition Physiology Genomics Department of Animal Sciences and Division of Nutritional SciencesUniversity of IllinoisUrbanaIL 61801USA.

Background:In rodents,research has revealed a role of liver X receptors(LXR) in controlling lipid homeostasis and regulating the synthesis of polyunsaturated fatty acids(PUFA).Recent data suggest that LXRB is the predominant LXR subtype in ruminant mammary cells,but its role in lipid metabolism is unknown.It was hypothesized that LXRB plays a role in lipid homeostasis via altering the synthesis of PUFA in the ruminant mammary gland.We used overexpression and knockdown of LXRB in goat primary mammary epithelial cells(GMEC) to evaluate abundance of lipogenic enzymes,fatty acid profiles,content of lipid stores and activity of the stearoyl-Co A desaturase(SCD1) promoter.Results:Overexpression of LXRB markedly upregulated the protein abundance of LXRB while incubation with si RNA targeting LXRB markedly decreased abundance of LXRB protein.Overexpression of LXRB plus T0901317(T09,a ligand for LXR) dramatically upregulated SCD1 and elongation of very long chain fatty acid-like fatty acid elongases 5–7(ELOVL 5–7),which are related to PUFA synthesis.Compared with the control,cells overexpressing LXRB and stimulated with T09 had greater concentrations of C16:0,16:1,18:1n7,18:1n9 and C18:2 as well as desaturation and elongation indices of C16:0.Furthermore,LXRB-overexpressing cells incubated with T09 had greater levels of triacylglycerol and cholesterol.Knockdown of LXRB in cells incubated with T09 led to downregulation of genes encoding elongases and desaturases.Knockdown of LXRB attenuated the increase in triacylglycerol and cholesterol that was induced by T09.In cells treated with dimethylsulfoxide,knockdown of LXRB increased the concentration of C16:0 at the expense of C18:0,while a significant decrease in C18:2 was observed in cells incubated with both si LXRB and T09.The abundance of sterol regulatory element binding transcription factor 1 precursor(p SREBP1) and its mature fragment(n SREBP1) was upregulated by T09,but not LXRB overexpression.In the cells cultured with T09,knockdown of LXRB downregulated the abundance

关键词： Elongase lipid homeostasis Liver X receptor Mammary gland Polyunsaturated fatty acids

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Disruption of hepatic lipid homeostasis is involved in valproate-induced hepatotoxicity

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中国药理学与毒理学杂志 2016年第10期30卷 1059-1059页

作者： BAI Xu-peng HONG Wei-peng YU Wei-bang HUANG Min JIN Jing School of Pharmaceutical Sciences Sun Yat-sen University

OBJECTIVE To investigate the mechanism underlying valproate(VPA)-induced hepatic hepatotoxicity.METHODS C57B/6J mice were given VPA at500 mg·kg-1·d-1by intragastric administration for 14 consecutive days,while the control group received the same volume of physiologic saline by intragastric administration for same days.Mice were sacrificed 24 h after the last administration.Blood samples were collected for plasma biochemical assays.Liver was fixed in 10%neutral buffered formalin for histopathological analysis,and RNA extraction.mR NA for selected genes expression encoding proteins key to fatty acid synthesis,triglyceride synthesis,fatty acid oxidation,phosphatidylcholine synthesis,and lipid uptake were measured using quantitative real-time PCR.RESULTS We found that VPA treatment induced hepatic injury in mice as evidenced by increased ALP,ATP,ASP,GGT,and LDH.Histopathological analysis of the liver in mice treated with VPA showed increased microvesicular steatosis in cytoplasm.More importantly,VPA treatment increased the m RNA expressions of sterol regulatory element binding protein(SREBP)-1c,peroxisome proliferator-activated receptor(PPAR)γ,diacylgycerol acyltransferase(DGAT)2,and cluster of differentiation(CD)36,while the mR NA levels of stearoyl-Co A desaturase(SCD)1,DGAT1,liver X receptorsα(LXRα),carnitine palmitoyltransferase(CPT)1,malonyl coenzyme A decarboxylase(MCD),uncoupling protein(UCP)2,phosphatidylethanolamine N-methyltransferase(PEMT),and pregnenolone X receptor(PXR)displayed significant decrease.CONCLUSION Our data showed that VPA induced disruption of hepatic lipid homeostasis,which could be helpful for a better under-standing of the mechanism underlying VPA-induced hepatotoxicity and for a better use of VPA.

关键词： VPA hepatic steatosis lipid homeostasis hepatotoxicity

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PITPNC1 promotes the thermogenesis of brown adipose tissue under acute cold exposure

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Science China(Life Sciences) 2022年第11期65卷 2287-2300页

作者： Guoqing Tang Chengxin Ma Liangkui Li Shaoyan Zhang Fengsheng Li Jin Wu Yesheng Yin Qing Zhu Yan Liang Ru Wang He Huang Tong-Jin Zhao Hongyuan Yang Peng Li Feng-Jung Chen Shanghai Key Laboratory of Metabolic Remodeling and Health Institute of Metabolism and Integrative BiologyInstitutes of Biomedical SciencesDepartment of Endocrinology and MetabolismZhongshan HospitalFudan UniversityShanghai 200438China State Key Laboratory of Membrane Biology and Tsinghua-Peking Center for Life Sciences Beijing Advanced Innovation Center for Structural BiologySchool of Life SciencesTsinghua UniversityBeijing 100084China School of Kinesiology Shanghai University of SportShanghai 200438China Shanghai Qi Zhi Institute Shanghai 200030China School of Biotechnology and Biomolecular Sciences the University of New South WalesSydneyNSW 2052Australia

Brown adipose tissue (BAT) plays an essential role in non-shivering thermogenesis. The phosphatidylinositol transfer protein, cytoplasmic 1 (PITPNC1) is identified as a lipid transporter that reciprocally transfers phospholipids between intracellular membrane structures. However, the physiological significance of PITPNC1 and its regulatory mechanism remain unclear. Here, we demonstrate that PITPNC1 is a key player in thermogenesis of BAT. While Pitpnc1^(−/−) mice do not differ with wildtype mice in body weight and insulin sensitivity on either chow or high-fat diet, they develop hypothermia when subjected to acute cold exposure at 4℃. The Pitpnc1^(−/−) brown adipocytes exhibit defective β-oxidation and abnormal thermogenesis-related metabolism pathways in mitochondria. The deficiency of lipid mobilization in Pitpnc1^(−/−) brown adipocytes might be the result of excessive accumulation of phosphatidylcholine and a reduction of phosphatidic acid. Our findings have uncovered significant roles of PITPNC1 in mitochondrial phospholipid homeostasis and BAT thermogenesis.

关键词： PITPNC1 thermogenesis acute cold exposure β-oxidation lipid homeostasis

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Thrombin increases the expression of cholesterol 25-hydroxylase in rat astrocytes after spinal cord injury

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Neural Regeneration Research 2023年第6期18卷 1339-1346页

作者： Chen Chen Huiyuan Ji Nan Jiang Yingjie Wang Yue Zhou Zhenjie Zhu Yuming Hu Yongjun Wang Aihong Li Aisong Guo Department of Rehabilitation Medicine Affiliated Hospital of Nantong UniversityNantongJiangsu ProvinceChina Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education Co-innovation Center of NeuroregenerationNantong UniversityNantongJiangsu ProvinceChina Department of Rehabilitation Medicine The Second Affiliated Hospital of Nantong UniversityNantongJiangsu ProvinceChina Department of Neurology Affiliated Hospital of Nantong UniversityNantongJiangsu ProvinceChina Department of Traditional Chinese Medicine Affiliated Hospital of Nantong UniversityNantongJiangsu ProvinceChina

Astrocytes are important cellular centers of cholesterol synthesis and metabolism that help maintain normal physiological function at the organism level.Spinal cord injury results in aberrant cholesterol metabolism by astrocytes and excessive production of oxysterols,which have profound effects on neuropathology.25-Hydroxycholesterol(25-HC),the main product of the membrane-associated enzyme cholesterol-25-hydroxylase(CH25H),plays important roles in mediating neuroinflammation.However,whether the abnormal astrocyte cholesterol metabolism induced by spinal cord injury contributes to the production of 25-HC,as well as the resulting pathological effects,remain unclear.In the present study,spinal cord injury-induced activation of thrombin was found to increase astrocyte CH25H expression.A protease-activated receptor 1 inhibitor was able to attenuate this effect in vitro and in vivo.In cultured primary astrocytes,thrombin interacted with protease-activated receptor 1,mainly through activation of the mitogen-activated protein kinase/nuclear factor-kappa B signaling pathway.Conditioned culture medium from astrocytes in which ch25h expression had been knocked down by siRNA reduced macrophage migration.Finally,injection of the protease activated receptor 1 inhibitor SCH79797 into rat neural sheaths following spinal cord injury reduced migration of microglia/macrophages to the injured site and largely restored motor function.Our results demonstrate a novel regulatory mechanism for thrombin-regulated cholesterol metabolism in astrocytes that could be used to develop anti-inflammatory drugs to treat patients with spinal cord injury.

关键词： 25-hydroxycholesterol astrocyte chemotaxis cholesterol metabolism cholesterol-25-hydroxylase lipid homeostasis macrophage PAR1 spinal cord injury thrombin

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Carboxylesterase 1 family knockout alters drug disposition and lipid metabolism

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Acta Pharmaceutica Sinica B 2023年第2期13卷 618-631页

作者： Changpei Gan Jing Wang Alejandra Martínez-Chávez Michel Hillebrand Niels de Vries Joke Beukers Els Wagenaar Yaogeng Wang Maria C.Lebre Hilde Rosing Sjoerd Klarenbeek Rahmen Bin Ali Colin Pritchard Ivo Huijbers Jos H.Beijnen Alfred H.Schinkel Division of Pharmacology the Netherlands Cancer InstituteAmsterdam 1066 CXthe Netherlands Department of Pharmacy&Pharmacology the Netherlands Cancer InstituteAmsterdam 1066 CXthe Netherlands Division of Pharmacoepidemiology and Clinical Pharmacology Utrecht Institute for Pharmaceutical SciencesUtrecht UniversityUtrecht 3584 CSthe Netherlands Experimental Animal Pathology Facility the Netherlands Cancer InstituteAmsterdam 1066 CXthe Netherlands Mouse Clinic for Cancer and Aging(MCCA)Transgenic Facility the Netherlands Cancer InstituteAmsterdam 1066 CXthe Netherlands

The mammalian carboxylesterase 1(Ces1/CES1)family comprises several enzymes that hydrolyze many xenobiotic chemicals and endogenous lipids.To investigate the pharmacological and physiological roles of Ces1/CES1,we generated Ces1 cluster knockout(Ces1^(-/-))mice,and a hepatic human CES1 transgenic model in the Ces1^(-/-)background(TgCES1).Ces1^(-/-)mice displayed profoundly decreased conversion of the anticancer prodrug irinotecan to SN-38 in plasma and tissues.TgCES1 mice exhibited enhanced metabolism of irinotecan to SN-38 in liver and kidney.Ces1 and hCES1 activity increased irinotecan toxicity,likely by enhancing the formation of pharmacodynamically active SN-38.Ces1^(-/-)mice also showed markedly increased capecitabine plasma exposure,which was moderately decreased in TgCES1 mice.Ces1^(-/-)mice were overweight with increased adipose tissue,white adipose tissue inflammation(in males),a higher lipid load in brown adipose tissue,and impaired blood glucose tolerance(in males).These phenotypes were mostly reversed in TgCES1 mice.TgCES1 mice displayed increased triglyceride secretion from liver to plasma,together with higher triglyceride levels in the male liver.These results indicate that the carboxylesterase 1 family plays essential roles in drug and lipid metabolism and detoxification.Ces1^(-/-)and TgCES1 mice will provide excellent tools for further study of the in vivo functions of Ces1/CES1 enzymes.

关键词： Ces1/CES1 enzymes Irinotecan Capecitabine Adipose tissue lipid homeostasis Inflammation Triglyceride mobilization Mouse models

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Polyphenols and pectin enriched golden kiwifruit (Actinidia chinensis) alleviates high fructose-induced glucolipid disorders and hepatic oxidative damage in rats:in association with improvement of fatty acids metabolism

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Food Science and Human Wellness 2023年第5期12卷 1872-1884页

作者： Aamina Alim Ting Li Tanzeela Nisar Zeshan Ali Daoyuan Ren Yueyue Liu Xingbin Yang Shaanxi Engineering Laboratory for Food Green Processing and Safety Control and Shaanxi Key Laboratory for Hazard Factors Assessment in Processing and Storage of Agricultural ProductsCollege of Food Engineering and Nutritional ScienceShaanxi Normal UniversityXi'an 710119China Faculty of Rehabilitation and Allied Health Sciences Riphah International UniversityLahore 54000Pakistan Department of Life sciences Barani InstitutionSahiwal 57000Pakistan

This study aimed to investigate the protective effects of fleshes from two Actinidia chinensis(ACF), pericarps from two A. chinensis(ACP), and fleshes with pericarps from two A. chinensis(ACFP)on high fructose(HF)-instigated dyslipidemia, hepatic steatosis, oxidative stress, insulin resistance, and fatty acid metabolism disorders in rats. In general, the above abnormalities were improved after 10 weeks intervention of ACF, ACP, and ACFP. Especially, ACFP considerably ameliorated HF-induced abnormal changes in body weight gain, serum TC, TG, LDL-C and HDL-C levels, as well as serum and hepatic SFAs, MUFAs and PUFAs contents. ACFP also alleviated HF-induced hyperglycemia and hyperinsulinemia, stabilized HF-caused increase in hepatic MDA and serum ALT, AST levels, and restored HF-declined hepatic T-SOD and GSH-Px activities. Besides, histopathology of the liver further endorsed the protective effects of ACFP on hepatocellular injury. Moreover, ACFP increased HF-dropped acetic, propionic and butyric acid levels. Overall, ACFP employs more efficacious protective effects against HF-induced metabolic disorders and liver damage than ACF and ACP. This study delivers a scientific foundation for developing kiwifruit(counting peel)-based dietary supplements for those with glucolipid-metabolic disorders and liver damage.

关键词： Actinidia chinensis peel lipid homeostasis Oxidative stress Insulin resistance Hepatocellular injury Fatty acid metabolism

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