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Metabolic-associated fatty liver disease from childhood to adulthood:State of art and future directions

World Journal of Hepatology 2022年第6期14卷 1087-1098页

作者： Francesca Lanzaro Stefano Guarino Elisabetta D'Addio Alessandra Salvatori JosèAlberto D'Anna Pierluigi Marzuillo Emanuele Miraglia del Giudice Anna Di Sessa Department of Woman Childand General and Specialized SurgeryUniversity of Campania“Luigi Vanvitelli”Naples 80138Italy

In 2020,an international group of experts proposed to replace the term of nonalcoholic fatty liver disease with metabolic-associated fatty liver disease(MAFLD).This recent proposal reflects the close association of fatty liver with metabolic derangements,as demonstrated by previous robust data.Several factors[including genetics,inflammation,metabolic abnormalities,insulin resistance(IR),obesity,prenatal determinants,and gut–liver axis]have been found to be involved in MAFLD pathophysiology,but this tangled puzzle remains to be clearly understood.In particular,IR has been recognized as a key player in metabolic impairments development in children with fatty liver.On this ground,MAFLD definition focuses on the pathophysiological basis of the disease,by emphasizing the crucial role of metabolic impairments in this condition.Although primarily developed for adults,MAFLD diagnostic criteria have been recently updated with an age-appropriate definition for sex and age percentiles,because of the increasing attention to cardiometabolic risk in childhood.To date,accumulating evidence is available on the feasibility of MAFLD definition in clinical practice,but some data are still conflicting in highly selected populations.Considering the growing prevalence worldwide of fatty liver and its close relationship with metabolic dysfunction both in children and adults with subsequent increased cardiovascular risk,early strategies for MAFLD identification,treatment and prevention are needed.Novel therapeutic insights for MAFLD based on promising innovative biological techniques are also emerging.We aimed to summarize the most recent evidence in this intriguing research area both in children and adults.

关键词： Metabolic dysfunction fatty Liver Pathophysiology Cardiovascular Risk Adults Children

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Advances in pediatric non-alcoholic fatty liver disease: From genetics to lipidomics

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World Journal of Clinical Pediatrics 2022年第3期11卷 221-238页

作者： Simona Riccio Rosa Melone Caterina Vitulano Pierfrancesco Guida Ivan Maddaluno Stefano Guarino Pierluigi Marzuillo Emanuele Miraglia del Giudice Anna Di Sessa Department of Woman ChildGeneral and Specialized SurgeryUniversity of Campania Luigi VanvitelliNaples 80138Italy

As a result of the obesity epidemic,non-alcoholic fatty liver disease(NAFLD)represents a global medical concern in childhood with a closely related increased cardiometabolic risk.Knowledge on NAFLD pathophysiology has been largely expanded over the last decades.Besides the well-known key NAFLD genes(including the I148M variant of the PNPLA3 gene,the E167K allele of the TM6SF2,the GCKR gene,the MBOAT7-TMC4 rs641738 variant,and the rs72613567:TA variant in the HSD17B13 gene),an intriguing pathogenic role has also been demonstrated for the gut microbiota.More interestingly,evidence has added new factors involved in the“multiple hits”theory.In particular,omics determinants have been highlighted as potential innovative markers for NAFLD diagnosis and treatment.In fact,different branches of omics including metabolomics,lipidomics(in particular sphingolipids and ceramides),transcriptomics(including micro RNAs),epigenomics(such as DNA methylation),proteomics,and glycomics represent the most attractive pathogenic elements in NAFLD development,by providing insightful perspectives in this field.In this perspective,we aimed to provide a comprehensive overview of NAFLD pathophysiology in children,from the oldest pathogenic elements(including genetics)to the newest intriguing perspectives(such as omics branches).

关键词： fatty Liver Genetics Lipidomics Pediatric

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fatty liver diseases,bile acids,and FXR

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Acta Pharmaceutica Sinica B 2016年第5期6卷 409-412页

作者： Yan Zhu Hongxia Liu Min Zhang Grace L.Guo Beijing Mentougou District Hospital School of Nursing Beijing University of Chinese Medicine Children's Liver Diseases Center 302 Military Hospital of China Department of Pharmacology and Toxicology Earnest Mario School of Pharmacy & Environmental and Occupational Health Science InstituteRutgers University

The prevalence of nonalcoholic fatty liver disease(NAFLD) worldwide has increased at an alarming rate,which will likely result in enormous medical and economic burden.NAFLD presents as a spectrum of liver diseases ranging from simple steatosis,nonalcoholic steatohepatitis(NASH),fibrosis,cirrhosis,and even to hepatocellular carcinoma(HCC).A comprehensive understanding of the mechanism(s) of NAFLD-to-NASH transition remains elusive with various genetic and environmental susceptibility factors possibly involved.An understanding of the mechanism may provide novel strategies in the prevention and treatment to NASH.Abnormal regulation of bile acid homeostasis emerges as an important mechanism to liver injury.The bile acid homeostasis is critically regulated by the farnesoid X receptor(FXR) that is activated by bile acids.FXR has been known to exert tissue-specific effects in regulating bile acid synthesis and transport.Current investigations demonstrate FXR also plays a principle role in regulating lipid metabolism and suppressing inflammation in the liver.Therefore,the future determination of the molecular mechanism by which FXR protects the liver from developing NAFLD may shed light to the prevention and treatment of NAFLD.

关键词： Nonalcoholic fatty liver disease Nonalcoholic steatohe patitis Liver lipid metabolism Bile acids Farnesoid X receptor

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fatty liver diseases, mechanisms, and potential therapeutic plant medicines

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Chinese Journal of Natural Medicines 2020年第3期18卷 161-168页

作者： ZHU Jia-Zhen YI Hong-Wei HUANG Wei PANG Tao ZHOU Hui-Ping WU Xu-Dong State Key Laboratory of Pharmaceutical Biotechnology School of Life SciencesNanjing UniversityNanjing 210023China Department of Pharmacology School of MedicineSoutheast UniversityNanjing 210009China State Key Laboratory of Natural Medicines China Pharmaceutical UniversityNanjing 210009China Department of Microbiology and Immunology and Mc Guire Veterans Affairs Medical Center Virginia Commonwealth UniversityRichmond 23218USA

The liver is an important metabolic organ and controls lipid, glucose and energy metabolism. Dysruption of hepatic lipid metabolism is often associated with fatty liver diseases, including nonalcoholic fatty liver disease(NAFLD), alcoholic fatty liver diseases(AFLD) and hyperlipidemia. Recent studies have uncovered the contribution of hormones, transcription factors, and inflammatory cytokines to the pathogenesis of dyslipidemia and fatty liver diseases. Moreover, a significant amount of effort has been put to examine the mechanisms underlying the potential therapeutic effects of many natural plant products on fatty liver diseases and metabolic diseases. We review the current understanding of insulin, thyroid hormone and inflammatory cytokines in regulating hepatic lipid metabolism, focusing on several essential transcription regulators, such as Sirtuins(SIRTs), Forkhead box O(FoxO), Sterol-regulatory element-binding proteins(SREBPs). We also discuss a few representative natural products with promising thereapeutic effects on fatty liver disease and dyslipidemia.

关键词： fatty liver disease Lipid metabolism Hormones Transcription factors Inflammatory cytokines Natural products

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Anti-hypercholesterolemic effect of Pistacia lentiscus fatty oil in egg yolk-fed rabbits: a comparative study with simvastatin

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Chinese Journal of Natural Medicines 2014年第8期12卷 561-566页

作者： Zouhir DJERROU Institute of Veterinary Sciences Pharmacology & Toxicology Laboratory Mentouri Constantine University

AIM: The current study was undertaken to assess anti-hyperlipidemic activity of Pistacia lentiscus fatty oil(PLFO) in rabbits following a hyperlipidemic diet. METHOD: Twenty healthy female(WNZ) rabbits were divided into four groups of five animals each:(a) normal control(NC group) receiving standard diet,(b) hyperlipidemic control(EY) group receiving standard diet and gavaged daily with egg yolk(10 mL),(c) hyperlipidemic + PLFO(EY + PLFO) group receiving as the EY group and treated daily with PLFO(2 mL/kg BW,(d) hyperlipidemic + simvastatin(EY + SVS) group receiving as the EY group and treated once daily with 2.5 mg/kg BW of simvastatin. At the end of the six-week experimental period, the lipidemic profiles of the different groups were investigated. RESULTS: In the EY group, the egg yolk resulted in a significant increase of total cholesterol(TC), triglycerides(TG), HDL-C, LDL-C, and the LDL-C/HDL-C ratio. Both the EY + PLFO and EY + SVS groups, when compared to the EY group, showed a significant decrease of TC, TG, LDL-C, and the LDL-C/HDL-C ratio. However, with respect to HDL-C the differences were not significant. The TGs were significantly lower(P fatty oil(PLFO) possesses anti-hyperlipidemic properties at least in reducing total cholesterol, LDL-cholesterol and triglycerides.

关键词： Pistacia lentiscus fatty oil, Anti-hperlipidemic activity Rabbits

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fatty liver is associated with an increased risk of diabetes and cardiovascular disease- Evidence from three different disease models: NAFLD, HCV and HIV

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World Journal of Gastroenterology 2016年第44期22卷 9674-9693页

作者： Amedeo Lonardo Stefano Ballestri Giovanni Guaraldi Fabio Nascimbeni Dante Romagnoli Stefano Zona Giovanni Targher Division of Internal Medicine and Metabolism Nuovo Ospedale Civile Sant'Agostino Estense - Department of Biomedical Metabolic and Neural Sciences University of Modena and Reggio Emilia and Azienda Ospedaliera of Modena Internal Medicine Pavullo Hospital Azienda Ospedaliera of Modena Section of Infectious Diseases Department of Medicine University of Modena Section of Endocrinology Diabetes and Metabolism Department of Medicine University and Azienda Ospedaliera Universitaria Integrata of Verona

fatty liver, which frequently coexists with necroinflammatory and fibrotic changes, may occur in the setting of nonalcoholic fatty liver disease(NAFLD) and chronic infections due to either hepatitis C virus(HCV) or human immunodeficiency virus(HIV). These three pathologic conditions are associated with an increased prevalence and incidence of cardiovascular disease(CVD) and type 2 diabetes(T2D). In this multidisciplinary clinical review, we aim to discuss the ever-expanding wealth of clinical and epidemiological evidence supporting a key role of fatty liver in the development of T2 D and CVD in patients with NAFLD and in those with HCV or HIV infections. For each of these three common diseases, the epidemiological features, pathophysiologic mechanisms and clinical implications of the presence of fatty liver in predicting the risk of incident T2 D and CVD are examined in depth. Collectively, the data discussed in this updated review, which follows an innovative comparative approach, further reinforce the conclusion that the presence of fatty/inflamed/fibrotic liver might be a shared important determinant for the development of T2 D and CVD in patients with NAFLD, HCV or HIV. This review may also open new avenues in the clinical and research arenas and paves the way for the planning of future, well-designed prospective and intervention studies.

关键词： Atherosclerosis Cardiovascular risk fatty liver Fibrosis Hepatitis C-associated dysmetabolic syndrome Hepatitis C virus Human immunodeficiency virus Nonalcoholic fatty liver disease Steatohepatitis Steatosis Virus-associated fatty liver disease

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Association of leukocyte telomere length with non-alcoholic fatty liver disease in patients with type 2 diabetes

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Chinese Medical Journal 2019年第24期132卷 2927-2933页

作者： Min Zhang Man-Li Hu Jiao-Jiao Huang San-Shan Xia Yan Yang Kun Dong Hubei Medical Evaluation and Continuing Education Office WuhanHubei 430000China Department of Endocrinology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei 430000China Department of Endocrinology Wuhan Fourth HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei 430000China

Background:Leukocyte telomere has been shown to be related to insulin resistance-related diseases,such as type 2 diabetes mellitus(T2DM)and non-alcoholic fatty liver disease(NAFLD).This cross-sectional study investigated the association of leukocyte telomere length(LTL)with NAFLD in T2DM patients.Methods:Clinical features were collected and LTL was measured by Southern blot-based terminal restriction fragment length analysis in 120 T2DM patients without NAFLD and 120 age-matched T2DM patients with NAFLD.NAFLD was clinically defined by manifestations of ultrasonography.The correlation between LTL and clinical and biochemical parameters were analyzed by Pearson correlation or Spearman correlation analysis.Factors for NAFLD in T2DM patients were identified using multiple logistic regressions.Results:LTL in T2DM patients with NAFLD were significantly longer than those without NAFLD(6400.2±71.8 base pairs[bp]vs.6023.7±49.5 bp,P<0.001),especially when diabetes duration was less than 2 years.Meanwhile,the trend of shorter LTL was associated with the increased diabetes duration in T2DM patient with NAFLD,but not in T2DM patients without NAFLD.Finally,LTL(odds ratio[OR]:1.001,95%confidence interval[CI]:1.000–1.002,P=0.001),as well as body mass index(OR:1.314,95%CI:1.169–1.477,P<0.001)and triglycerides(OR:1.984,95%CI:1.432–2.747,P<0.001),had a significant association with NAFLD status in T2DM patients.Conclusions:T2DM patients with NAFLD had a significantly longer LTL than those without NAFLD.The longer LTL was especially evident in the early stage of T2DM,indicating that longer LTL may be used as a biomarker for NAFLD in T2DM patients.

关键词： Non-alcoholic fatty liver disease Telomere Type 2 diabetes mellitus

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High prevalence of nonalcoholic fatty liver in patients with idiopathic venous thromboembolism

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World Journal of Gastroenterology 2010年第48期16卷 6119-6122页

作者： Matteo Nicola Dario Di Minno Antonella Tufano Anna Rusolillo Giovanni Di Minno Giovanni Tarantino Department of Clinical and Experimental Medicine Federico II University Medical School of Naples

AIM:To assess the prevalence of nonalcoholic fatty liver disease (NAFLD) in patients with idiopathic venous thromboembolism (VTE). METHODS:In a case-control study,after excluding subjects with well-consolidated risk factors for VTE,idiopathic VTE was documented in 138 consecutive patients who were referred to our department. Two hundred and seventy-six healthy sex/age/body-massindex-matched subjects,without any clinical/instrumental evidence of VTE,served as controls. All underwent a clinical/laboratory/ultrasound assessment for the presence of metabolic syndrome and NAFLD. RESULTS:NAFLD was detected in 112/138 cases (81%) and in 84/276 controls (30%) [risk ratio:2.7,95% confidence interval (CI):2.2-3.2,P < 0.0001]. Metabolic syndrome and smoking habit were more prevalent in patients with idiopathic VTE. The high prevalence of NAFLD in VTE was also confirmed after adjustment for inherited thrombophilia. NAFLD was clearly predicted by VTE (odds ratio:1.8,95% CI:1.2-2.7,P < 0.0001).

关键词： Thromboembolism Metabolic syndrome Nonalcoholic fatty liver disease

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fatty liver in hepatitis C patients post-sustained virological response with direct-acting antivirals

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World Journal of Gastroenterology 2018年第11期24卷 1269-1277页

作者： Mazen Noureddin Micaela M Wong Tsuyoshi Todo Shelly C Lu Arun J Sanyal Edward A Mena fatty Liver Program Cedars-Sinai Medical CenterLos AngelesCA 90048United States Division of Digestive and Liver Diseases Cedars-Sinai Medical CenterLos AngelesCA 90048United States California Liver Research Institute PasadenaCA 91105United States Comprehensive Transplant Center Department of SurgeryCedars-Sinai Medical CenterLos AngelesCA 90048United States Division of Digestive and Liver Diseases Cedars-Sinai Medical CenterLos AngelesCA 90048United States Division of Gastroenterology Hepatology and NutritionDepartment of Internal MedicineSchool of MedicineVirginia Commonwealth UniversityRichmondVA 23298United States

AIM To determine steatosis and fibrosis prevalence in hepatitis C patients after a sustained virological response achieved with direct-acting antivirals.METHODS Transient elastography with controlled attenuation parameter(CAP) was used to assess hepatic steatosis post-sustained virological response(SVR);the CAP technology was not available in the United States at study initiation.Liver stiffness/fibrosis was measured before and 47 wk after treatment completion.Patients with genotype 3 and patients with cirrhosis were excluded.RESULTS One hundred and one patients were included in the study.Post-SVR there were decreases from baseline in alanine aminotransferase(ALT)(63.1 to 17.8 U/L),aspartate aminotransferase(51.8 to 21.5 U/L) and fibrosis score(7.4 to 6.1 k Pa)(P fatty liver is very common in hepatitis C virus(HCV) patients post-SVR.These patients continue to have elevated mean fibrosis score(≥ 7 k Pa) compared to those without fatty liver;some have advanced fibrosis.Long term follow up is needed to assess steatosis and fibrosis in HCV patients post-SVR.

关键词： Nonalcoholic fatty liver disease Hepatitis C Fibrosis Steatosis Sustained virological response Direct-acting antivirals

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A kinetic model for a single step biodiesel production from a high free fatty acid (FFA) biodiesel feedstock over a solid heteropolyacid catalyst

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Green Energy & Environment 2019年第3期4卷 328-341页

作者： Aashish Gaurav Stéphane Dumas Chau T.Q.Mai Flora T.T.Ng Department of Chemical Engineering University of Waterloo

Production of biodiesel from yellow grease(waste cooking oil and waste animal fats) is fast emerging as a promising alternative to address the twin challenges before the biodiesel industry today-fluctuation in prices of vegetable oil and the food versus fuel debate. Yellow grease has a high percentage of free fatty acids(FFA) and proves to be an unsuitable feedstock for biodiesel production from commercially viable alkalicatalyzed production systems due to saponification problems.'Green' methodologies based on heterogeneous solid acid catalyzed reactions have the potential to simultaneously promote esterification and transesterification reactions of yellow grease to produce biodiesel without soap formation and offer easy catalyst separation without generation of toxic streams. This paper presents kinetic studies for the conversion of model yellow grease feeds to biodiesel using a heteropolyacid supported on alumina(HSiW/Al2O3) using a batch autoclave. Three model yellow grease feeds were prepared using canola oil with added FFA such as palmitic, oleic and linoleic acid. A pseudo homogeneous kinetic model for the parallel esterification and transesterification was developed. The rate constants and activation parameters for esterification and transesterification reactions for the model yellow grease feeds were determined. The rate constants for esterification are higher than the transesterification rate constants. The kinetic model was validated using the experimental biodiesel data obtained from processing a commercial yellow grease feed. The kinetic model could be used to design novel processes to convert various low-value waste oils, fats and non-food grade oils to sustainable biodiesel.

关键词： Yellow grease Canola oil Free fatty acids Heteropolyacid Kinetics for esterification and transesterification

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