| Background:Coronary heart disease(CHD)is closely related to liver metabolic disorders.Metabolic(dysfunction)-associated fatty liver disease(MAFLD),formerly known as nonalcoholic fatty liver disease(NAFLD),is a newly proposed concept,emphasizing the liver diseases caused by metabolic dysfunction.MAFLD shares common metabolic risk factors with cardiovascular disease.This study aims to investigate the association between liver metabolic disorders and adverse cardiovascular outcomes in CHD patients with wellcontrolled LDL-C.Methods:CHD patients with LDL-C<1.8mmol/L were divided into MAFLD and nonMAFLD groups.Propensity score matching(PSM)balanced baseline differences between the two groups.The primary endpoint was major adverse cardiac and cerebrovascular events(MACCE).The cumulative event-free survival rates of MAFLD and non-MAFLD groups were analyzed with Kaplan-Meier analysis.Cox proportional risk model was used to calculate hazard ratio and 95%confidential interval.Results:After PSM,the baseline characteristics of MAFLD patients and non-MAFLD patients had no significant difference.MAFLD patients exhibited a significantly higher cumulative incidence of MACCE than those without MAFLD(9.6%versus 6.6%,p<0.05).Consistently,Cox proportional hazards regression analysis found MAFLD patients had a significantly increased risk for MACCE(HR 1.48,95%confidential interval(CI)1.04-2.1,p<0.05).Further research found that Fibrosis-4(FIB-4)was a prognostic factor.MAFLD patients were divided into two groups with and without advanced liver fibrosis according to FIB-4≥3.25 or FIB-4<3.25.Advanced liver fibrosis staged by the FIB-4 index was associated with an elevated risk for MACCE(HR 2.42,95%CI 1.12-5.22,p<0.05)compared to those without advanced liver fibrosis.Conclusion:MAFLD was an independent risk factor for MACCE among CHD patients with well-controlled LDL-C levels.Advanced liver fibrosis evaluated by FIB-4 index was associated with increased risk of MACCEs in MAFLD patients.Background:The first part of the study found that metabolic disorder is associated with poor prognosis in patients with coronary heart disease,and liver fibrosis stage of patients with fatty liver disease is associated with the risk of adverse events.Liver fibrosis is an important pathological process in liver metabolic disorders.Fibrosis-4(FIB-4)index,calculated by age,aspartate aminotransferase(AST),alanine aminotransferase(ALT)and platelet count,is a well-recognized,noninvasive tool to evaluate liver fibrosis.The first part of the study found that the FIB-4 index may be the main prognostic indicator for patients with coronary heart disease and liver metabolic disorders.We aim to further explore the value of the FIB-4 index for coronary heart disease in patients with acute coronary syndrome(ACS).Methods:This study included 6563 patients,with the primary endpoint being the major adverse cardiac and cerebrovascular event(MACCE),composed of all-cause death,myocardial infarction(MI),and ischemic stroke(IS).Patients were divided into three groups according to literature-based FIB-4 cut-offs:<1.45,1.45-3.25 and≥3.25.Kaplan-Meier analysis was used to compare the cumulative event-free survival rates among groups.Restricted cubic spline(RCS)was used to analyze the correlation between FIB-4 index as a continuous variable and outcome events.The Cox proportional risk regression model was used to evaluate the hazard ratio and 95%confidence interval between the FIB-4 index and the outcomes.Results:During the median 2.4-year follow-up,a total of 270 MACCEs were recorded.Compared to patients with low FIB-4 scores,patients with intermediate and high FIB4 scores were significantly associated with elevated MACCE risks(HR 1.33,95%CI 1.02-1.74;HR 2.59,95%CI 1.21-4.23).Elevated FIB-4 index was associated with increased risks of all-cause death,cardiac death and MI.FIB-4 index was not associated with an elevated risk of major bleeding.RCS showed that FIB-4 index as continuous variables was positively associated with increased adjusted risk of MACCE regardless of the presence of type 2 diabetes(T2DM).Furthermore,incorporating FIB-4 index into a risk prediction model constructed by traditional risk factors significantly raised the predictive performance.The results were consistent in subgroups with and without T2DM as the similar analyses were performed in subgroups.Conclusions:Liver fibrosis staged by FIB-4 index was correlated with an increased risk of MACCE,mortality,and MI in ACS.FIB-4 index may help risk stratification of patients independent of T2DM status.Background:The first and second parts of this paper indicate that liver metabolic disorders are associated with poor prognosis in patients with coronary heart disease.Therefore,treating liver metabolic disorders is of great significance for the prevention and treatment of coronary heart disease.The third part of this paper further explores potential therapeutic targets for liver metabolic disorders through basic research.Impaired endo-lysosome-mediated protein degradation is observed in a variety of metabolic disorders,such as atherosclerosis,type 2 diabetes mellitus and NAFLD.Small integral membrane protein of lysosome/late endosome(SIMPLE)is a regulator of endosome-to-lysosome trafficking and cell signaling.However,the role that SIMPLE plays in liver metabolic disorders remains unknown.Here we investigated SIMPLE function in liver metabolic disorders.Methods:In vitro Simple-knockdown cell model was constructed and received metabolic stimulation.Cellular lipid deposition was detected by Nile red staining.Lipid synthesis/transport and inflammation related gene expression levels were detected by quantitative real-time PCR.Hepatocyte-specific Simple-knockout mice(Simple-HKO)were constructed,liver metabolic disorders mouse models were induced with high-fat(HFD)diet,high-fat-high-cholesterol(HFHC)diet,and methionine-choline-deficient(MCD)diet.Glycolipid metabolism was evaluated by body weight,liver weight,blood glucose,glucose tolerance,serum lipid levels,and serum liver enzyme levels.Hepatic lipid deposition was detected by oil red O staining and hematoxylin&eosin staining.Liver fibrosis was detected by picrosirius red staining.Hepatic inflammatory cell infiltration was detected by CD11b staining.The changes of cellular signaling pathways and gene expression levels in Simple-HKO mice were analyzed by transcriptome.The molecular mechanism was explored with western blot,immune precipitation and other molecular biology experiments.Results:This study found in vitro knockdown of SIMPLE significantly aggravated lipid accumulation,inflammation in hepatocytes treated with metabolic stimulation.Consistently,in vivo experiments showed that liver-specific Simple-knockout(SimpleHKO)mice exhibited more severe HFD-,HFHC-,and MCD-induced steatosis,glucose intolerance,inflammation,and fibrosis than those fed with normal-chow diet.Meanwhile,RNA-sequencing demonstrated the up-regulated signaling pathways and signature genes involved in lipid metabolism,inflammation and fibrosis in SimpleHKO mice compared to control mice under metabolic stress.Mechanically,we found SIMPLE regulate the lysosomal degradation of epidermal growth factor receptor(EGFR).SIMPLE deficiency results in dysregulated degradation of EGFR,subsequently hyperactivated EGFR phosphorylation,exaggerating liver metabolic disorders development.Moreover,we further demonstrated that using EGFR inhibitor or silencing EGFR expression could ameliorate lipid accumulation induced by the knockdown of SIMPLE.Conclusions:SIMPLE ameliorated liver metabolic disorders by prompting lysosomal degradation of EGFR and can also be a potential therapeutic candidate for liver metabolic disorders. |
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