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Lingguizhugan Decoction, a Chinese herbal formula, improves insulin resistance in overweight/obese subjects with non-alcoholic fatty liver disease: a translational approach

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Frontiers of Medicine 2022年第5期16卷 745-759页

作者： Liang Dai Jingjuan Xu Baocheng Liu Yanqi Dang Ruirui Wang Lijie Zhuang Dong Li Lulu Jiao Jianying Wang Lei Zhang Linda LDZhong Wenjun Zhou Guang Ji Institute of Digestive diseases Longhua HospitalShanghai University of Traditional Chinese MedicineShanghai 200032China Clinical Research Academy Peking University Shenzhen HospitalShenzhen 518032China Department of Integrated Traditional and Western Medicine Jinling HospitalMedical School of Nanjing UniversityNanjing 210002China Shanghai Innovation Centre of TCM Health Service Shanghai University of Traditional Chinese MedicineShanghai 201203China Sanlin Health Centre of Pudong New District Shanghai 200120China Zhangjiang Health Centre of Pudong New District Shanghai 201203China Beicai Health Centre of Pudong New District Shanghai 201204China Hong Kong Chinese Medicine Study Centre Hong Kong Baptist UniversityHong Kong 999077China

Lingguizhugan Decoction(LGZG)has been investigated in basic studies,with satisfactory effects on insulin resistance in non-alcoholic fatty liver disease(NAFLD).This translational approach aimed to explore the effect and underlying mechanism of LGZG in clinical setting.A randomized,double-blinded,placebo-controlled trial was performed.A total of 243 eligible participants with NAFLD were equally allocated to receive LGZG(two groups:standard dose and low dose)or placebo for 12 weeks on the basis of lifestyle modifications.The primary efficacy variable was homeostasis model assessment of insulin resistance(HOMA-IR).Analyses were performed in two populations in accordance with body mass index(BMI;overweight/obese,BMI 24 kg/m^(2);lean,BMI<24 kg/m^(2)).For overweight/obese participants,low-dose LGZG significantly decreased their HOMA-IR level compared with placebo(0.19(1.47)versus 0.08(1.99),P=0.038).For lean subjects,neither dose of LGZG showed a superior effect compared with placebo.Methylated DNA immunoprecipitation sequencing and real-time qPCR found that the DNA N6-methyladenine modification levels of protein phosphatase 1 regulatory subunit 3A(PPP1R3A)and autophagy related 3(ATG3)significantly increased after LGZG intervention in overweight/obese population.Low-dose LGZG effectively improved insulin resistance in overweight/obese subjects with NAFLD.The underlying mechanism may be related to the regulation of DNA N6-methyladenine modification of PPP1R3A and ATG3.Lean subjects may not be a targeted population for LGZG.

关键词： insulin resistance non-alcoholic fatty liver disease Chinese herbal medicine randomized controlled trial DNA N6-methyladenine modification

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Clinical impact and mechanisms of hepatitis B virus infection concurrent with non-alcoholic fatty liver disease

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Chinese Medical Journal 2022年第14期135卷 1653-1663页

作者： Xin Tong Yu Song Shengxia Yin Jian Wang Rui Huang Chao Wu Junping Shi Jie Li Department of Infectious diseases Nanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjingJiangsu 210008China Institute of Viruses and Infectious diseases Nanjing UniversityNanjingJiangsu 210008China Department of Hepatology Zhejiang Chinese Medical UniversityHangzhouZhejiang 310053China Department of Hepatology The Affiliated Hospital of Hangzhou Normal UniversityHangzhouZhejiang 310015China

Chronic hepatitis B(CHB)virus infection is an important threat to global health despite the administration of vaccines and the use of antiviral treatments.In recent years,as the prevalence of obesity and metabolic syndrome has increased,non-alcoholic fatty liver disease(NAFLD)in patients with CHB has become more common.Both diseases can lead to liver fibrosis and even hepatocellular carcinoma,but the risk of dual etiology,outcome,and CHB combined with NAFLD is not fully elucidated.In this review,we assess the overlapping prevalence of NAFLD and CHB,summarize recent studies of clinical and basic research related to potential interactions,and evaluate the progressive changes of treatments for CHB patients with NAFLD.This review increases the understanding of the relationship and mechanisms of interaction between steatosis and hepatitis B virus infection,and it provides new strategies for the future clinical management and treatment of CHB combined with NAFLD.

关键词： Chronic hepatitis B non-alcoholic fatty liver disease Steatosis Mechanism

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Bile acids and sphingolipids in non-alcoholic fatty liver disease

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Chinese Medical Journal 2022年第10期135卷 1163-1171页

作者： Kaitlyn G.Jackson Grayson W.Way Huiping Zhou Department of Microbiology and Immunology Virginia Commonwealth University School of MedicineRichmondVA 23298USA Center for Clinical and Translational Research Virginia Commonwealth University School of MedicineRichmondVA 23298USA Central Virginia Veterans Healthcare System RichmondVA 23249USA.

non-alcoholic fatty liver disease (NAFLD) is one of the fastest-growing diseases, and its global prevalence is estimated to increase >50% by 2030. NAFLD is comorbid with metabolic syndrome, obesity, type 2 diabetes, and insulin resistance. Despite extensive research efforts, there are no pharmacologic or biological therapeutics for the treatment of NAFLD. Bile acids and sphingolipids are well-characterized signaling molecules. Over the last few decades, researchers have uncovered potential mechanisms by which bile acids and sphingolipids regulate hepatic lipid metabolism. Dysregulation of bile acid and sphingolipid metabolism has been linked to steatosis, inflammation, and fibrosis in patients with NAFLD. This clinical observation has been recapitulated in animal models, which are well-accepted by experts in the hepatology field. Recent transcriptomic and lipidomic studies also show that sphingolipids are important players in the pathogenesis of NAFLD. Moreover, the identification of bile acids as activators of sphingolipid-mediated signaling pathways established a novel theory for bile acid and sphingolipid biology. In this review, we summarize the recent advances in the understanding of bile acid and sphingolipid-mediated signaling pathways as potential contributors to NAFLD. A better understanding of the pathologic effects mediated by bile acids and sphingolipids will facilitate the development of new diagnostic and therapeutic strategies for NAFLD.

关键词： Bile acids Sphingolipids non-alcoholic fatty liver disease non-alcoholic steatohepatitis

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Severity of non-alcoholic fatty liver disease is a risk factor for developing hypertension from prehypertension

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Chinese Medical Journal 2023年第13期136卷 1591-1597页

作者： Qirui Song Qianhui Ling Luyun Fan Yue Deng Qiannan Gao Ruixue Yang Shuohua Chen Shouling Wu Jun Cai Hypertension Center Fuwai HospitalState Key Laboratory of Cardiovascular Disease of ChinaNational Center for Cardiovascular Diseases of ChinaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100037China State Key Laboratory of Cardiovascular disease of China Fuwai HospitalNational Center for Cardiovascular Diseases of ChinaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100037China Department of Cardiology Kailuan General HospitalTangshanHebei 063000China

Background:There is little published evidence about the role of non-alcoholic fatty liver disease(NAFLD)in the progression from prehypertension to hypertension.This study was conducted to investigate the association of NAFLD and its severity with the risk of hypertension developing from prehypertension.Methods:The study cohort comprised 25,433 participants from the Kailuan study with prehypertension at baseline;those with excessive alcohol consumption and other liver diseases were excluded.NAFLD was diagnosed by ultrasonography and stratified as mild,moderate,or severe.Univariable and multivariable Cox proportional hazard regression was used to calculate the hazard ratios(HRs)and 95%confidence intervals(CIs)of incident hypertension according to the presence and 3 categories of severity of NAFLD.Results:During a median of 12.6 years of follow-up,10,638 participants progressed to hypertension from prehypertension.After adjusting for multiple risk factors,patients with prehypertension and NAFLD had a 15%higher risk of incident hypertension than those without NAFLD(HR=1.15,95%CI 1.10-1.21).Moreover,the severity of NAFLD was associated with the incidence of hypertension,which was higher in patients with more severe NAFLD(HR=1.15[95%CI 1.10-1.21]in the mild NAFLD group;HR=1.15[95%CI 1.07-1.24]in the moderate NAFLD group;and HR=1.20[95%CI 1.03-1.41]in the severe NAFLD group).Subgroup analysis indicated that age and baseline systolic blood pressure may modify this association.Conclusions:NAFLD is an independent risk factor for hypertension in patients with prehypertension.The risk of incident hypertension increases with the severity of NAFLD.

关键词： Hypertension non-alcoholic fatty liver disease Prehypertension

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Appraisal of treatment outcomes in integrative medicine using metabonomics:Taking non-alcoholic fatty liver disease with spleen deficiency syndrome as an example

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Journal of Integrative Medicine 2022年第6期20卷 524-533页

作者： Liang Dai Jing-juan Xu Wen-jun Zhou Ai-ping Lü Guang Ji Clinical Research Academy Peking University Shenzhen HospitalPeking UniversityShenzhen 518032Guangdong ProvinceChina Institute of Digestive disease Longhua HospitalShanghai University of Traditional Chinese MedicineShanghai 200032China Department of Integrated Traditional and Western Medicine Jinling HospitalSchool of MedicineNanjing UniversityNanjing 210002Jiangsu ProvinceChina Academy of Integrative Medicine Shanghai University of Traditional Chinese MedicineShanghai 201203China School of Chinese Medicine Hong Kong Baptist UniversityHong Kong 999077China

Objective:Appraisal of treatment outcomes in integrative medicine is a challenge due to a gap between the concepts of Western medicine(WM)disease and traditional Chinese medicine(TCM)syndrome.This study presents an approach for the appraisal of integrative medicine that is based on targeted metabolomics.We use non-alcoholic fatty liver disease with spleen deficiency syndrome as a test case.Methods:A patient-reported outcome(PRO)scale was developed based on literature review,Delphi consensus survey,and reliability and validity test,to quantitatively evaluate spleen deficiency syndrome.Then,a metabonomic foundation for the treatment of non-alcoholic fatty liver disease with spleen deficiency syndrome was identified via a longitudinal interventional trial and targeted metabolomics.Finally,an integrated appraisal model was established by identifying metabolites that responded in the treatment of WM disease and TCM syndrome as positive outcomes and using other aspects of the metabonomic foundation as independent variables.Results:Ten symptoms and signs were included in the spleen deficiency PRO scale.The internal reliability,content validity,discriminative validity and structural validity of the scale were all qualified.Based on treatment responses to treatments for WM disease(homeostasis model assessment of insulin resistance)or TCM syndrome(spleen deficiency PRO scale score)from a previous randomized controlled trial,two cohorts comprised of 30 participants each were established for targeted metabolomics detection.Twenty-five metabolites were found to be involved in successful treatment outcomes to both WM and TCM,following quantitative comparison and multivariate analysis.Finally,the model of the integrated appraisal system was exploratively established using binary logistic regression;it included 9 core metabolites and had the prediction probability of 83.3%.Conclusion:This study presented a new and comprehensive research route for integrative appraisal of treatment outcomes for WM disease and TCM syndrome.Critica

关键词： Complementary and alternative medicine Integrative medicine Patient-reported outcome measures Metabolomics non-alcoholic fatty liver disease Spleen deficiency syndrome

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Interaction between mucus layer and gut microbiota in non-alcoholic fatty liver disease:Soil and seeds

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Chinese Medical Journal 2023年第12期136卷 1390-1400页

作者： Binbin Zhang Jie Li Jinlong Fu Li Shao Luping Yang Junping Shi Department of Translational Medicine Platform The Affiliated Hospital of Hangzhou Normal UniversityHangzhouZhejiang 310015China Department of School of Life Sciences Zhejiang University of Traditional Chinese MedicineHangzhouZhejiang 310053China Department of Infectious disease Nanjing Drum Tower HospitalAffiliated Hospital of Medical SchoolNanjing UniversityNanjingJiangsu 210008China Department of School of Clinical Medicine Hangzhou Normal UniversityHangzhouZhejiang 311121China Department of Fourth School of Clinical Medicine Zhejiang Chinese Medical UniversityHangzhouZhejiang 310053China Department of Infectious&Hepatology diseases Metabolic Disease CenterThe Affiliated Hospital of Hangzhou Normal UniversityHangzhouZhejiang 310015China

The intestinal mucus layer is a barrier that separates intestinal contents and epithelial cells,as well as acts as the"mucus layer-soil"for intestinal flora adhesion and colonization.Its structural and functional integrity is crucial to human health.Intestinal mucus is regulated by factors such as diet,living habits,hormones,neurotransmitters,cytokines,and intestinal flora.The mucus layer’s thickness,viscosity,porosity,growth rate,and glycosylation status affect the structure of the gut flora colonized on it.The interaction between"mucus layer-soil"and"gut bacteria-seed"is an important factor leading to the pathogenesis of non-alcoholic fatty liver disease(NAFLD).Probiotics,prebiotics,fecal microbiota transplantation(FMT),and wash microbial transplantation are efficient methods for managing NAFLD,but their long-term efficacy is poor.FMT is focused on achieving the goal of treating diseases by enhancing the"gut bacteria-seed".However,a lack of effective repair and management of the"mucus layer-soil"may be a reason why"seeds"cannot be well colonized and grow in the host gut,as the thinning and destruction of the"mucus layer-soil"is an early symptom of NAFLD.This review summarizes the existing correlation between intestinal mucus and gut microbiota,as well as the pathogenesis of NAFLD,and proposes a new perspective that"mucus layer-soil"restoration combined with"gut bacteria-seed"FMT may be one of the most effective future strategies for enhancing the long-term efficacy of NAFLD treatment.

关键词： non-alcoholic fatty liver disease Gut microbiome Fecal microbiota transplantation Intestinal barrier Intestinal mucus layer

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non-invasive tests of non-alcoholic fatty liver disease

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Chinese Medical Journal 2022年第5期135卷 532-546页

作者： Guanlin Li Xinrong Zhang Huapeng Lin Lilian Yan Liang Grace Lai-Hung Wong Vincent Wai-Sun Wong Department of Medicine and Therapeutics The Chinese University of Hong KongHong KongChina State Key Laboratory of Digestive disease The Chinese University of Hong KongHong KongChina Medical Data Analytics Centre The Chinese University of Hong KongHong KongChina

For the detection of steatosis,quantitative ultrasound imaging techniques have achieved great progress in past years.Magnetic resonance imaging proton density fat fraction is currently the most accurate test to detect hepatic steatosis.Some blood biomarkers correlate with non-alcoholic steatohepatitis,but the accuracy is modest.Regarding liver fibrosis,liver stiffness measurement by transient elastography(TE)has high accuracy and is widely used across the world.Magnetic resonance elastography is marginally better than TE but is limited by its cost and availability.Several blood biomarkers of fibrosis have been used in clinical trials and hold promise for selecting patients for treatment and monitoring treatment response.This article reviews new developments in the non-invasive assessment of non-alcoholic fatty liver disease(NAFLD).Accumulating evidence suggests that various non-invasive tests can be used to diagnose NAFLD,assess its severity,and predict the prognosis.Further studies are needed to determine the role of the tests as monitoring tools.We cannot overemphasize the importance of context in selecting appropriate tests.

关键词： fatty liver non-alcoholic fatty liver disease non-alcoholic steatohepatitis liver fibrosis Cirrhosis Transient elastography FibroScan Magnetic resonance imaging

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Roles of organelle-specific autophagy in hepatocytes in the development and treatment of non-alcoholic fatty liver disease

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Chinese Medical Journal 2022年第14期135卷 1673-1681页

作者： Yizhi Zhang Yu Chen Fourth Department of liver disease(Difficult and Complicated liver diseases and Artificial liver Center) Beijing You’an Hospital Affiliated to Capital Medical UniversityBeijing 100069China Beijing Municipal Key Laboratory of liver Failure and Artificial liver Treatment Research Beijing 100069China

non-alcoholic fatty liver disease(NAFLD)is a disorder of lipid metabolism.The lipotoxic intermediates of lipid metabolism cause mitochondrial dysfunction and endoplasmic reticulum stress.Organelle-specific autophagy is responsible for the removal of dysfunctional organelles to maintain intracellular homeostasis.Lipophagy contributes to lipid turnover by degrading lipid droplets.The level of autophagy changes during the course of NAFLD,and the activation of hepatocyte autophagy might represent a method of treating NAFLD.

关键词： Autophagy Lipophagy Mitophagy Reticulophagy non-alcoholic fatty liver disease

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Protective Roles of Shilajit in Modulating Resistin,Adiponectin,and Cytokines in Rats with non-alcoholic fatty liver disease

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Chinese Journal of Integrative Medicine 2022年第6期28卷 531-537页

作者： Baran Ghezelbash Nader Shahrokhi Mohammad Khaksari Gholamreza Asadikaram Maryam Shahrokhi Sara Shirazpour Physiology Research Center Kerman University of Medical SciencesKerman***Iran Endocrinology and Metabolism Research CenterKerman University of Medical SciencesKerman***Iran Department of Biochemistry School of MedicineKerman University of Medical SciencesKerman***Iran Department of Medical Science School of DentistryShiraz University of Medical SciencesShiraz713414336Iran Department of Physiology and Pharmacology Faculty of MedicineKerman University of Medical SciencesKerman***Iran

Objective:To evaluate the effect of Shilajit,a medicine of Ayurveda,on the serum changes in cytokines and adipokines caused by non-alcoholic fatty liver disease(NAFLD).Methods:After establishing fatty liver models by feeding a high-fat diet(HFD)for 12 weeks,35 Wistar male rats were randomly divided into5 groups,including control(standard diet),Veh(HFD+vehicle),high-dose Shilajit[H-Sh,HFD+250 mg/(kg·d)Shilajit],low-dose Shilajit[L-Sh,HFD+150 mg/(kg·d)Shilajit],and pioglitazone[HFD+10 mg/(kg·d)pioglitazone]groups,7 rats in each group.After 2-week of gavage administration,serum levels of glucose,insulin,interleukin1 beta(IL-1β),IL-6,IL-10,tumor necrosis factor-alpha(TNF-α),adiponectin,and resistin were measured,and insulin resistance index(HOMA-IR)was calculated.Results:After NAFLD induction,the serum level of IL-10 significantly increased and serum IL-1β,TNF-αlevels significantly decreased by injection of both doses of Shilajit and pioglitazone(P<0.05).Increases in serum glucose level and homeostasis model of HOMA-IR were reduced by L-Sh and H-Sh treatment in NAFLD rats(P<0.05).Both doses of Shilajit increased adiponectin and decreased serum resistin levels(P<0.05).Conclusion:The probable protective role of Shilajit in NAFLD model rats may be via modulating the serum levels of IL-1β,TNF-α,IL-10,adipokine and resistin,and reducing of HOMA-IR.

关键词： non-alcoholic fatty liver disease Shilajit adipokines cytokines glucose insulin dietary supplement Ayurvedic medicine

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Estimating global prevalence,incidence,and outcomes of nonalcoholic fatty liver disease from 2000 to 2021:systematic review and meta-analysis

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Chinese Medical Journal 2022年第14期135卷 1682-1691页

作者： Jiaye Liu Ye Tian Xia Fu Chunyang Mu Menglin Yao Yinyun Ni Yong Liu Zhihui Li Department of Thyroid and Parathyroid Surgery West China HospitalSichuan UniversityChengduSichuan 610000China Laboratory of Thyroid and Parathyroid diseases Frontiers Science Center for Disease-Related Molecular NetworkWest China HospitalSichuan UniversityChengduSichuan 610000China State Key Laboratory of Biotherapy and Cancer Center West China HospitalSichuan University and Collaborative Innovation CenterChengduSichuan 610000China Respiratory Health Institute Frontiers Science Center for Disease Molecular NetworkWest China HospitalSichuan UniversityChengduSichuan 610000China Department of Ultrasound West China Hospital of Sichuan UniversityChengduSichuan 610000China Department of Outpatients West China HospitalSichuan UniversityChengduSichuan 610000China Department of liver Surgery and liver Transplantation Center West China HospitalSichuan UniversityChengduSichuan 610000China Department of Gastroenterological Surgery West China HospitalSichuan UniversityChengduSichuan 610000China

Background:The increasing burden of non-alcoholic fatty liver disease(NAFLD)worldwide imposes an emerging public health issue.We perform the current study to estimate the global prevalence,incidence,disease progression,and clinical outcomes of NAFLD.Methods:A systematic search was conducted in Medline,Embase,Web of Science,Google Scholar,and Cochrane CENTRAL that screened articles in English language published from January 2000 to December 2021.NAFLD prevalence,incidence,rate of disease progression,and outcomes were calculated with the DerSimonian-Laird random effects model with arcsine transformation.Results:Our search identified 59,156 records,of which 578 studies fulfilled our inclusion criteria.The overall prevalence of NAFLD was 29.38%(95%confidence interval[CI]28.09-30.69)regardless of the diagnostic techniques.Looking at the group in which the diagnosis was made by ultrasound exclusively,the pooled prevalence was 30.49%(95%CI 29.55-31.43).NAFLD has become more prevalent during the year 2011-2021(31.63%,95%CI 30.23-33.04)compared with year 2000-2010(27.94%,95%CI 26.23-29.69).The pooled estimation of non-alcoholic steatohepatitis prevalence was 8.26%(95%CI 1.13-21.01),46.49%(95%CI 35.93-57.20),and 46.72%(95%CI 37.57-55.98)in general population,NAFLD patients,and severe/morbidly obese patients,respectively.Based on a total of 110,142 newly developed NAFLD patients,the pooled incident rate was estimated as 46.24 cases per 1000 person-years(95%CI 43.21-49.30).In patients with NAFLD,the incident rate of hepatocellular carcinoma was 1.46(95%CI 0.90-2.03)cases per 1000 person-years.The overall pooled estimate of NAFLD related mortality was 23.91(95%CI 13.55-37.18)death per 1000 person-years.Conclusions:The prevalence of NAFLD is increasing globally.It is contributing to poor clinical outcomes including hepatocellular carcinoma and death.Rising awareness and urgent actions are warranted to control the NAFLD pandemic across the globe.Registration:PROSPERO,No.CRD42020171104.

关键词： Incidence non-alcoholic fatty liver disease non-alcoholic steatohepatitis Outcome Prevalence

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