Secreted Frizzled-Related Protein 5 Mediates Wnt5a Expression in Microcystin-Leucine-Arginine-Induced Liver Lipid Metabolism Disorder in Mice

Objective Microcystin-leucine-arginine(MC-LR)exposure induces lipid metabolism disorders in the liver.Secreted frizzled-related protein 5(SFRP5)is a natural antagonist of winglesstype MMTV integration site family,member 5A(Wnt5a)and an anti-inflammatory adipocytokine.In this study,we aimed to investigate whether MC-LR can induce lipid metabolism disorders in hepatocytes and whether SFRP5,which has anti-inflammatory effects,can alleviate the effects of hepatic lipid metabolism by inhibiting the Wnt5a/Jun N-terminal kinase(JNK)pathway.Methods We exposed mice to MC-LR in vivo to induce liver lipid metabolism disorders.Subsequently,mouse hepatocytes that overexpressed SFRP5 or did not express SFRP5 were exposed to MC-LR,and the effects of SFRP5 overexpression on inflammation and Wnt5a/JNK activation by MC-LR were observed.Results MC-LR exposure induced liver lipid metabolism disorders in mice and significantly decreased SFRP5 mRNA and protein levels in a concentration-dependent manner.SFRP5 overexpression in AML12cells suppressed MC-LR-induced inflammation.Overexpression of SFRP5 also inhibited Wnt5a and phosphorylation of JNK.Conclusion MC-LR can induce lipid metabolism disorders in mice,and SFRP5 can attenuate lipid metabolism disorders in the mouse liver by inhibiting Wnt5a/JNK signaling.

Mechanistic study of lipid metabolism disorders in diabetic kidney disease treated with GLQMP based on network pharmacology,molecular docking and in vitro experiments

Background:In this study,we used network pharmacology and molecular docking combined with vitro experiments to explore the potential mechanism of action of Gualou Qumai pill(GLQMP)against DKD.Methods:We screened effective compounds and drug targets using Chinese medicine systemic pharmacology database and analysis platform and Chinese medicine molecular mechanism bioinformatics analysis tools;and searched for DKD targets using human online Mendelian genetics and gene cards.The potential targets of GLQMP for DKD were obtained through the intersection of drug targets and disease targets.Cytoscape software was applied to build herbal medicine-active compound-target-disease networks and analyze them;protein-protein interaction networks were analyzed using the STRING database platform;gene ontology and Kyoto Encyclopedia of Genes and Genomes were used for gene ontology and gene and genome encyclopedia to enrich potential targets using the DAVID database;and the AutoDock Vina 1.1.2 software for molecular docking of key targets with corresponding key components.In vitro experiments were validated by CCK8,oil red O staining,TC,TG,RT-qPCR,and Western blot.Results:Through network pharmacology analysis,a total of 99 potential therapeutic targets of GLQMP for DKD and the corresponding 38 active compounds were obtained,and 5 core compounds were identified.By constructing the protein-protein interaction network and performing network topology analysis,we found that PPARA and PPARG were the key targets,and then we molecularly docked these two key targets with the 38 active compounds,especially the 5 core compounds,and found that PPARA and PPARG had good binding ability with a variety of compounds.In vitro experiments showed that GLQMP was able to ameliorate HK-2 cell injury under high glucose stress,improve cell viability,reduce TC and TG levels as well as decrease the accumulation of lipid droplets,and RT-qPCR and Western blot confirmed that GLQMP was able to promote the expression levels of PPARA and PPARG.Conclusion:Overall,this study revealed the active compounds,important targets and possible mechanisms of GLQMP treatment for DKD,and conducted preliminary verification experiments on its correctness,provided novel insights into the treatment of DKD by GLQMP.

Huangqin decoction alleviates lipid metabolism disorders and insulin resistance in nonalcoholic fatty liver disease by triggering Sirt1/NF-κB pathway

BACKGROUND Nonalcoholic fatty liver disease(NAFLD)is a clinicopathological entity characterized by intrahepatic ectopic steatosis.As a consequence of increased consumption of high-calorie diet and adoption of a sedentary lifestyle,the incidence of NAFLD has surpassed that of viral hepatitis,making it the most common cause of chronic liver disease globally.Huangqin decoction(HQD),a Chinese medicinal formulation that has been used clinically for thousands of years,has beneficial outcomes in patients with liver diseases,including NAFLD.However,the role and mechanism of action of HQD in lipid metabolism disorders and insulin resistance in NAFLD remain poorly understood.AIM To evaluate the ameliorative effects of HQD in NAFLD,with a focus on lipid metabolism and insulin resistance,and to elucidate the underlying mechanism of action.METHODS High-fat diet-induced NAFLD rats and palmitic acid(PA)-stimulated HepG2 cells were used to investigate the effects of HQD and identify its potential mechanism of action.Phytochemicals in HQD were analyzed by highperformance liquid chromatography(HPLC)to identify the key components.RESULTS Ten primary chemical components of HQD were identified by HPLC analysis.In vivo,HQD effectively prevented rats from gaining body and liver weight,improved the liver index,ameliorated hepatic histological aberrations,decreased transaminase and lipid profile disorders,and reduced the levels of pro-inflammatory factors and insulin resistance.In vitro studies revealed that HQD effectively alleviated PA-induced lipid accumulation,inflammation,and insulin resistance in HepG2 cells.In-depth investigation revealed that HQD triggers Sirt1/NF-κB pathwaymodulated lipogenesis and inflammation,contributing to its beneficial actions,which was further corroborated by the addition of the Sirt1 antagonist EX-527 that compromised the favorable effects of HQD.CONCLUSION In summary,our study confirmed that HQD mitigates lipid metabolism disorders and insulin resistance in NAFLD by triggering the Sirt1/NF-κB pathway.

Uridine diphosphate glucuronosyltransferase 1A1 prevents the progression of liver injury

BACKGROUND Uridine diphosphate glucuronosyltransferase 1A1(UGT1A1)plays a crucial role in metabolizing and detoxifying endogenous and exogenous substances.However,its contribution to the progression of liver damage remains unclear.AIM To determine the role and mechanism of UGT1A1 in liver damage progression.METHODS We investigated the relationship between UGT1A1 expression and liver injury through clinical research.Additionally,the impact and mechanism of UGT1A1 on the progression of liver injury was analyzed through a mouse model study.RESULTS Patients with UGT1A1 gene mutations showed varying degrees of liver damage,while patients with acute-onchronic liver failure(ACLF)exhibited relatively reduced levels of UGT1A1 protein in the liver as compared to patients with chronic hepatitis.This suggests that low UGT1A1 levels may be associated with the progression of liver damage.In mouse models of liver injury induced by carbon tetrachloride(CCl_(4))and concanavalin A(ConA),the hepatic levels of UGT1A1 protein were found to be increased.In mice with lipopolysaccharide or liver steatosis-mediated liver-injury progression,the hepatic protein levels of UGT1A1 were decreased,which is consistent with the observations in patients with ACLF.UGT1A1 knockout exacerbated CCl_(4)-and ConA-induced liver injury,hepatocyte apoptosis and necroptosis in mice,intensified hepatocyte endoplasmic reticulum(ER)stress and oxidative stress,and disrupted lipid metabolism.CONCLUSION UGT1A1 is upregulated as a compensatory response during liver injury,and interference with this upregulation process may worsen liver injury.UGT1A1 reduces ER stress,oxidative stress,and lipid metabolism disorder,thereby mitigating hepatocyte apoptosis and necroptosis.

Study on the Correlation between Metabolic Syndrome and Colorectal

Metabolic syndrome has been widely recognized in various studies as being intricately linked to the initiation and progression of colorectal adenoma. The potential pathways through which metabolic syndrome influences colorectal adenoma encompass chronic inflammation, insulin resistance, oxidative stress, and dysbiosis of the intestinal flora. This review aims to consolidate the understanding of the association between metabolic syndrome and colorectal adenoma, elucidating the interconnected mechanisms between different metabolic syndrome-related disorders and colorectal adenoma. By shedding light on these connections, this review offers valuable insights for the preventive strategies targeting colorectal adenoma.

Multi-omics: Opportunities for research on mechanism of type 2 diabetes mellitus

Type 2 diabetes mellitus(T2DM)is a burdensome global disease.In-depth understanding of its mechanism will help to optimize diagnosis and treatment,which reduces the burden.Multi-omics research has unparalleled advantages in contributing to the overall understanding of the mechanism of this chronic metabolic disease.In the past two decades,the study of multi-omics on T2DMrelated intestinal flora perturbation and plasma dyslipidemia has shown tremendous potential and is expected to achieve major breakthroughs.The regulation of intestinal flora in diabetic patients has been confirmed by multiple studies.The use of metagenomics,16S RNA sequencing,and metabolomics has comprehensively identified the overall changes in the intestinal flora and the metabolic disturbances that could directly or indirectly participate in the intestinal flora-host interactions.Lipidomics combined with other“omics”has characterized lipid metabolism disorders in T2DM.The combined application and crossvalidation of multi-omics can screen for dysregulation in T2DM,which will provide immense opportunities to understand the mechanisms behind T2DM.

Association Analysis of Hyperlipidemia with the 28-Day All-Cause Mortality of COVID-19 in Hospitalized Patients

Objective This study aimed to determine the association of hyperlipidemia with clinical endpoints among hospitalized patients with COVID-19,especially those with pre-existing cardiovascular diseases(CVDs)and diabetes.Methods This multicenter retrospective cohort study included all patients who were hospitalized due to COVID-19 from 21 hospitals in Hubei province,China between December 31,2019 and April 21,2020.Patients who were aged<18 or≥85 years old,in pregnancy,with acute lethal organ injury(e.g.,acute myocardial infarction,severe acute pancreatitis,acute stroke),hypothyroidism,malignant diseases,severe malnutrition,and those with normal lipid profile under lipid-lowering medicines(e.g,statin,niacin,fenofibrate,gemfibrozil,and ezetimibe)were excluded.Propensity score matching(PSM)analysis at 1:1 ratio was performed to minimize baseline differences between patient groups of hyperlipidemia and non-hyperlipidemia.PSM analyses with the same strategies were further conducted for the parameters of hyperlipidemia in patients with increased triglyceride(TG),increased low・density lipoprotein cholesterol(LDL-C),and decreased high-density lipoprotein cholesterol(HDL-C).Mixed-effect Cox model analysis was performed to investigate the associations of the 28-days all-cause deaths of COVID-19 patients with hyperlipidemia and the abnormalities of lipid parameters.The results were verified in male,female patients,and in patients with pre-existing CVDs and type 2 diabetes.Results Of 1094S inpatients confirmed as COVID-19,there were 9822 inpatients included in the study,comprising 3513(35.8%)cases without hyperlipidemia and 6309(64.2%)cases with hyperlipidemia.Based on a mixed-effect Cox model after PSM at 1:1 ratio,hyperlipidemia was not associated with increased or decreased 28-day all-cause death[adjusted hazard ratio(HR),1.17(95%C/,0.95-1.44),P二0.151].Wb found that the parameters of hyperlipidemia were not associated with the risk of 28-day all-cause mortality[adjusted HR,1.23(95%CI,0.98-1.55),P=0.075 in TG increase group;0.78(95%CI,0.57-1.07),P=0.123 in LDL-C increase group;and 1.12(95%CI,0.9-1.39),P=0.299 in HDL-C decrease group,respectively].Hyperlipidemia was also not significantly associated with the increased mortality of COVID-19 in patients accompanied with CVDs or type 2 diabetes,and in both male and female cohorts.Conclusion Our study support that the imbalanced lipid profile is not significantly associated with the 28-day all-cause mortality of COVID-19 patients,even in those accompanied with CVDs or diabetes.Similar results were also obtained in subgroup analyses of abnormal lipid parameters.Therefore,hyperlipidemia might be not a major causative factor for poor outcome of COVID-19,which provides guidance for the intervention of inpatients during the epidemic of COVID-19.

Gentiopicroside targets PAQR3 to activate the PI3K/AKT signaling pathway and ameliorate disordered glucose and lipid metabolism

The obstruction of post-insulin receptor signaling is the main mechanism of insulin-resistant diabetes.Progestin and adipoQ receptor 3(PAQR3),a key regulator of inflammation and metabolism,can negatively regulate the PI3 K/AKT signaling pathway.Here,we report that gentiopicroside(GPS),the main bioactive secoiridoid glycoside of Gentiana manshurica Kitagawa,decreased lipid synthesis and increased glucose utilization in palmitic acid(PA) treated HepG2 cells.Additionally,GPS improved glycolipid metabolism in streptozotocin(STZ) treated high-fat diet(HFD)-induced diabetic mice.Our findings revealed that GPS promoted the activation of the PI3 K/AKT axis by facilitating DNA-binding protein 2(DDB2)-mediated PAQR3 ubiquitinated degradation.Moreover,results of surface plasmon resonance(SPR),microscale thermophoresis(MST) and thermal shift assay(TSA) indicated that GPS directly binds to PAQR3.Results of molecular docking and cellular thermal shift assay(CETSA) revealed that GPS directly bound to the amino acids of the PAQR3 NH2-terminus including Leu40,Asp42,Glu69,Tyr125 and Ser129,and spatially inhibited the interaction between PAQR3 and the PI3 K catalytic subunit(P110α) to restore the PI3 K/AKT signaling pathway.In summary,our study identified GPS,which inhibits PAQR3 expression and directly targets PAQR3 to restore insulin signaling pathway,as a potential drug candidate for the treatment of diabetes.

Critical roles of FTO-mediated mRNA m6A demethylation in regulating adipogenesis and lipid metabolism: Implications in lipid metabolic disorders

The goal this review is to clarify the effects of the fat mass and obesity-associated protein (FTO) in lipid metabolism regulation and related underlying mechanisms through the FTO-mediated demethylation of m6A modification. FTO catalyzes the demethylation of m6A to alter the processing, maturation and translation of the mRNAs of lipid-related genes. FTO overexpression in the liver promotes lipogenesis and lipid droplet (LD) enlargement and suppresses CPT-1–mediated fatty acid oxidation via the SREBP1c pathway, promoting excessive lipid storage and nonalcoholic fatty liver diseases (NAFLD). FTO enhances preadipocyte differentiation through the C/EBPβ pathway, and facilitates adipogenesis and fat deposition by altering the alternative splicing of RUNX1T1, the expression of PPARγ and ANGPTL4, and the phosphorylation of PLIN1, whereas it inhibits lipolysis by inhibiting IRX3 expression and the leptin pathway, causing the occurrence and development of obesity. Suppression of the PPARβ/δ and AMPK pathways by FTO-mediated m6A demethylation damages lipid utilization in skeletal muscles, leading to the occurrence of diabetic hyperlipidemia. m6A demethylation by FTO inhibits macrophage lipid influx by downregulating PPARγ protein expression and accelerates cholesterol efflux by phosphorylating AMPK, thereby impeding foam cell formation and atherosclerosis development. In summary, FTO-mediated m6A demethylation modulates the expression of lipid-related genes to regulate lipid metabolism and lipid disorder diseases.

EGb761, an extract of Ginkgo biloba leaves, reduces insulin resistance in a high-fat-fed mouse model

EGb761,a standardized and well-defined product extract of Ginkgo biloba leaves,has beneficial effects on the treatment of multiple diseases,including diabetes and dyslipidemia.However,it is still unclear whether EGb761 can increase insulin sensitivity.The objectives of the present study are to evaluate the effects of EGb761 on insulin sensitivity in an obese and insulinresistant mouse model,established through chronic feeding of C57BL/6J mice with a high-fat diet(HFD),and to explore potential mechanisms.Mice fed with HFD for 18 weeks(starting from 4 weeks of age)developed obesity,dyslipidemia(as indicated by biochemical measurements of blood glucose,triglyceride(TG),total cholesterol(TC),and free fatty acids(FFA)),and insulin resistance(as determined by the oral glucose tolerance test(OGTT)and the homeostasis model assessment of insulin resistance(HOMA-IR)index),compared to control mice fed with a standard laboratory chow.Oral treatment of the HFD-fed mice with EGb761,at low(100 mg/kg),medium(200 mg/kg),or high(400 mg/kg)doses,via oral gavage(once daily)for 8 weeks(starting from 26 weeks of age)dose-dependently enhanced glucose tolerance in OGTT,and decreased both the insulin levels(by 29%,55%,and 70%,respectively),and the HOMA-IR index values(by 50%,69%,and 80%,respectively).EGb761 treatment also ameliorated HFD-induced obesity,dyslipidemia,and liver injury,as indicated by decreases in body weight(by 4%,11%,and 16%,respectively),blood TC levels(by 23%,32%,and 37%,respectively),blood TG levels(by 17%,23%,and 33%,respectively),blood FAA levels(by 35%,38%,and 46%,respectively),and liver index(liver weight/body weight)values(by 12.8%,25%,and 28%,respectively)in the low,medium,and high EGb761 dose groups,respectively.In further mechanism studies,EGb761 was found to protect hepatic insulin receptor b and insulin receptor substrate 1 from HFD-induced degradation,and to keep the AMP-activated protein kinase,which plays a crucial role in reducing lipotoxicity,from HFD-induced inactivation.We conclude that EGb761 can effectively reduce HFD-induced insulin resistance and ameliorate other symptoms of the metabolic syndrome.