摘要：
BACKGROUND: Curcumin nicotinate (Curtn), derived from curcumin and niacin, reduces serum LDL-C levels, partly due to its influence on PCSK9. This study investigates IDOL's role in Curtn's lipid-lowering effects. OBJECTIVE: To elucidate Curtn's regulation of the IDOL/LDLR pathway and potential molecular mechanisms in hepatocytes. METHODS: Differential metabolites in Curtn-treated HepG2 cells were identified via LC-MS. Molecular docking assessed Curtn's affinity with IDOL. Cholesterol content and LDLR expression effects were studied in high-fat diet Wistar rats. In vitro evaluations determined Curtn's influence on IDOL overexpression's LDL-C uptake and LDLR expression in hepatocytes. RESULTS: Lipids were the main differential metabolites in Curtn-treated HepG2 cells. Docking showed Curtn's higher affinity to IDOL's FERM domain compared to curcumin, suggesting potential competitive inhibition of IDOL's binding to LDLR. Curtn decreased liver cholesterol in Wistar rats and elevated LDLR expression. During in vitro experiments, Curtn significantly enhanced the effects of IDOL overexpression in HepG2 cells, leading to increased LDL-C uptake and elevated expression of LDL receptors. CONCLUSION: Curtn modulates the IDOL/LDLR pathway, enhancing LDL cholesterol uptake in hepatocytes. Combined with its PCSK9 influence, Curtn emerges as a potential hyperlipidemia therapy.
摘要：
Curcumin nicotinate (Curtn) is a synthesized ester derivative of curcumin and niacin. Our previous study has shown that Curtn lowers serum low-density lipoprotein cholesterol (LDL-C) levels in apoE(-/-) mice and promotes LDL-C uptake into HepG2 cells in vitro. The present study was to test the hypothesis that Curtn decreases serum LDL-C levels through decreased expression of pro-protein convertase subtilisin/kexin type 9 (PCSK9) and subsequent increase in LDL receptor expression. Male Wistar rats on high-fat diet (HFD) were treated with Curtn or rosuvastatin. Curtn or rosuvastatin treatment significantly decreased serum levels of total cholesterol (TC) and LDL-C in rats on HFD with increased liver LDL receptor expression. LDL-C-lowering effect of Curtn was not observed in LDL receptor deficient (LDLR(-/-)) mice on HFD, while rosuvastatin still decreased serum lipid levels in LDLR(-/-) mice, indicating that the reduction of serum LDL-C levels by Curtn treatment was LDL receptor-dependent. Curtn treatment also significantly decreased the protein expression of PCSK9 in Wistar rats and LDLR(-/-) mice. In HepG2 cells with overexpression of human PCSK9, Curtn treatment significantly increased LDL-C uptakes into hepatocytes, and increased LDL receptor distribution on cell surface in association with decreased PCSK9 protein expression. RNAi-LDLR significantly attenuated the effect of Curtn on LDLR distribution on cell surface. These data indicates that Curtn would decrease serum LDL-C level at least partially through inhibition of PCSK9 expression, and subsequent increase in LDL receptor expression and distribution in hepatocytes, serving as a potential novel compound to treat hyperlipidemia.
期刊：
JOURNAL OF MEMBRANE BIOLOGY,2020年253(2):101-108 ISSN：0022-2631
通讯作者：
Long, Shi-yin;Zhang, CP
作者机构：
[Wang, Chu-yao; Long, Shi-yin; Long, SY; Li, Bo-jie; Zhang, Cai-ping; Jiang, Su-su] Univ South China, Dept Biochem & Mol Biol, Med Coll, Hengyang 421001, Hunan, Peoples R China.;[Chen, Hao] Univ South China, Affiliated Hosp 1, Dept Clin Lab, Hengyang 421001, Hunan, Peoples R China.;[Tuo, Qin-hui] Hunan Univ Chinese Med, State Key Lab Chinese Med Powder & Med Innovat Hu, Div Stem Cell Regulat & Applicat, Changsha 410208, Hunan, Peoples R China.;[Liao, Duan-fang] Hunan Univ Chinese Med, State Key Lab Chinese Med Powder & Med Innovat Hu, Changsha 410208, Hunan, Peoples R China.
通讯机构：
[Long, SY; Zhang, CP ] U;Univ South China, Dept Biochem & Mol Biol, Med Coll, Hengyang 421001, Hunan, Peoples R China.
关键词：
KIF16B;Kinesin;Endocytic trafficking;Cholesterol transport
摘要：
As a member of the kinesin-3 family, kinesin family member 16B (KIF16B) has a characteristic PhoX homology (PX) domain that binds to membranes containing phosphatidylinositol-3-phosphate (PI(3)P) and moves along microtubule filaments to the plus end via a process regulated by coiled coils in the stalk region in various cell types. The physiological function of KIF16B supports the transport of intracellular cargo and the formation of endosomal tubules. Ras-related protein (Rab) coordinates many steps of membrane transport and are involved in the regulation of KIF16B-mediated vesicle trafficking. Data obtained from clinical research suggest that KIF16B has a potential effect on the disease processes in intellectual disability, abnormal lipid metabolism, and tumor brain metastasis. In this review, we summarize recent advances in the structural and physiological characteristics of KIF16B as well as diseases associated with KIF16B disorders, and speculating its role as a potential adaptor for intracellular cholesterol trafficking. Graphic
作者机构：
[Wu, Juanying; Xiao, Lihua] Univ South China, Affiliated Hosp 2, Dept Clin Lab, Hengyang, Hunan, Peoples R China.;[Tian, Ying; Long, Shiyin; Zhang, Caiping; Xiao, Lihua] Univ South China, Med Coll Hengyang, Dept Biochem & Mol Biol, Hengyang, Hunan, Peoples R China.;[Li, Na] Hunan Univ Chinese Med, Affiliated Hosp 2, Dept Pathol, Changsha, Hunan, Peoples R China.;[Chen, Wuzhe] Yong Zhou Vocat Tech Coll, Dept Biotechnol, Yongzhou, Hunan, Peoples R China.;[Long, Shiyin] Univ South China, Dept Biotechnol, Hengyang, Hunan, Peoples R China.
通讯机构：
[Long, SY ] U;Univ South China, Dept Biotechnol, Hengyang, Hunan, Peoples R China.
关键词：
HbA1c;HDL subclasses;Metabolic syndrome
摘要：
Background: Metabolic syndrome (MS) is characterized by a constellation of metabolic disorders. Hyperglycemia and dyslipidemia are the major risk factors of MS. Here we performed a study to explore the association between glycated hemoglobin A1c (HbA1c) and high-density lipoprotein (HDL) subclasses in patients with MS. Methods: We included 101 MS patients and 77 healthy subjects in this study. Blood tests were executed to assess the blood glucose and lipid indicators, including HbAlc, fasting plasma glucose (FPG), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apo- lipoprotein D-100 (aPoB(100)), pre beta(1)-HDL, HDL3b, aaPoB(100)/AI, apolipoprotein AI (apoAI), HDL2b and HDL2a. Multi- variate linear regression was used to explore potential relationship between HDL subclasses and HbA1c. Results: Compared with control group, the levels of HbA1c, FPG, TG, TC, LDL-C, apoB(100), pre beta(1)-HDL, HDL3b, apoB(100)/AI and LDL-C/HDL-C were significantly increased in MS subjects (p < 0.01), while plasma concentrations of HDL-C, apoAI, HDL2b and HDL2a were significantly decreased in MS subjects (p < 0.01). With the increase of whole blood HbA1c levels in MS subjects, pre beta(1)-HDL was elevated gradually, while HDL2a was decreased gradually. Conclusions: Blood HbA1c level is associated with the changes in HDL subclass distribution in patients with MS.
作者机构：
[Yang, Hui-xian] Univ South China, Med Coll, Inst Cardiovasc Dis, 28 Changsheng Rd, Hengyang 421001, Hunan, Peoples R China.;[Liao, Duan-fang; Chen, Jian-xiong; Tuo, Qin-hui] Hunan Univ Chinese Med, Div Stem Cell Regulat & Applicat, State Key Lab Chinese Med Powder & Med Innovat Hu, 300 Xueshi Rd, Changsha 410208, Hunan, Peoples R China.;[Liao, DF; Tian, Ying; Long, Shi-yin; Yang, Hui-xian; Zhang, Cai-ping; Zhang, Min] Univ South China, Med Coll, Dept Biochem & Mol Biol, 28 W Changsheng Rd, Hengyang 421001, Hunan, Peoples R China.;[Chen, Jian-xiong] Univ Mississippi, Med Ctr, Dept Pharmacol & Toxicol, University, MS 38677 USA.
通讯机构：
[Liao, DF ; Zhang, CP] U;Univ South China, Med Coll, Dept Biochem & Mol Biol, 28 W Changsheng Rd, Hengyang 421001, Hunan, Peoples R China.
关键词：
Dyslipidemia;IDOL;LDL-C;LDLR;PCSK9;SREBP2
摘要：
The SREBP2/LDLR pathway is sensitive to cholesterol content in the endoplasmic reticulum (ER), while membrane low-density lipoprotein receptor (LDLR) is influenced by sterol response element binding protein 2 (SREBP2), pro-protein convertase subtilisin/kexin type 9 (PCSK9) and inducible degrader of LDLR (IDOL). LDL-C, one of the risk factors in cardiovascular disease, is cleared through endocytosis recycling of LDLR. Therefore, we propose that a balance between LDLR endocytosis recycling and PCSK9-mediated and IDOL-mediated lysosomal LDLR degradation is responsible for cholesterol homeostasis in the ER. For statins that decrease serum LDL-C levels via cholesterol synthesis inhibition, the mechanism by which the statins increase the membrane LDLR may be regulated by cholesterol homeostasis in the ER.
摘要：
Obesity is defined as a chronic and excessive growth of adipose tissue. It has been associated with a high risk for development and progression of obesity-associated malignancies, while adipokines may mediate this association. Adiponectin is an adipose tissue-derived adipokines, with significant anti-diabetic, anti-inflammatory, anti-atherosclerotic and anti-proliferative properties. Plasma adiponectin levels are decreased in obese individuals, and this feature is closely correlated with development of several metabolic, immunological and neoplastic diseases. Recent studies have shown that prostate cancer patients have lower serum adiponectin levels and decreased expression of adiponectin receptors in tumor tissues, which suggests plasma adiponectin level is a risk factor for prostate cancer. Furthermore, exogenous adiponectin has exhibited therapeutic potential in animal models. In this review, we focus on the potential role of adiponectin and the underlying mechanism of adiponectin in the development and progression of prostate cancer. Exploring the signaling pathways linking adiponectin with tumorigenesis might provide a potential target for therapy.
