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Emerging novel targets for nonalcoholic fatty liver disease treatment: Evidence from recent basic studies

World Journal of Gastroenterology 2023年第1期29卷 75-95页

作者： Guang-Yan Wang Xiao-Yan Zhang Chun-Jiong Wang You-Fei Guan Department of Physiology and Pathophysiology Tianjin Medical UniversityTianjin 300070China The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics Tianjin 300070China NHC Key Laboratory of Hormones and Development Chu Hsien-I Memorial Hospital and Tianjin Institute of EndocrinologyTianjin 300070China Health Science Center East China Normal UniversityShanghai 200241China Advanced Institute for Medical Sciences Dalian Medical UniversityDalian 116044Liaoning ProvinceChina Department of Physiology and Pathophysiology School of Basic Medical SciencesDalian Medical UniversityDalian 116044Liaoning ProvinceChina Dalian Key Laboratory for Nuclear Receptors in Major Metabolic diseases Dalian 116044Liaoning ProvinceChina

nonalcoholic fatty liver disease(NAFLD),a leading chronic disease worldwide,affects approximately a quarter of the global *** steatohepatitis(NASH)is an advanced form of NAFLD and is more likely to progress to liver fibrosis than simple *** is also identified as the most rapidly growing cause of hepatocellular *** in the past decade,several phase II/III clinical trials have shown promising results in the use of novel drugs targeting lipid synthase,farnesoid X receptor signaling,peroxisome proliferatoractivated receptor signaling,hepatocellular injury,and inflammatory signaling,proven pharmaceutical agents to treat NASH are still ***,continuous exploration of the mechanism underlying the pathogenesis of NAFLD and the identification of novel therapeutic targets remain urgent tasks in the *** the current review,we summarize studies reported in recent years that not only provide new insights into the mechanisms of NAFLD development but also explore the possibility of treating NAFLD by targeting newly identified signaling *** also discuss evidence focusing on the intrahepatic targets involved in the pathogenesis of NAFLD as well as extrahepatic targets affecting liver metabolism and function.

关键词： nonalcoholic fatty liver disease nonalcoholic steatohepatitis Pharmaceutical strategies liver microenvironment Gut-liver axis Adipose tissue-liver axis

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Immunotherapy for nonalcoholic fatty liver disease-related hepatocellular carcinoma:Lights and shadows

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World Journal of Gastrointestinal Oncology 2022年第9期14卷 1622-1636页

作者： Federico Costante Carlo Airola Francesco Santopaolo Antonio Gasbarrini Maurizio Pompili Francesca Romana Ponziani Internal Medicine and Gastroenterology-Hepatology Unit Fondazione Policlinico Universitario Agostino Gemelli IRCCSRoma 00168Italy Catholic University Largo Francesco Vito 100168 RomaItaly

About one-fourth of adults globally suffer from nonalcoholic fatty liver disease(NAFLD), which is becoming a leading cause of chronic liver disease worldwide. Its prevalence has rapidly increased in recent years, and is projected to increase even more. NAFLD is a leading cause of hepatocellular carcinoma(HCC), the sixth-most prevalent cancer worldwide and the fourth most common cause of cancer-related death. Although the molecular basis of HCC onset in NAFLD is not completely known, inflammation is a key player. The tumor microenvironment(TME) is heterogeneous in patients with HCC, and is characterized by complex interactions between immune system cells, tumor cells and other stromal and resident liver cells. The etiology of liver disease plays a role in controlling the TME and modulating the immune response. Markers of immune suppression in the TME are associated with a poor prognosis in several solid tumors. Immunotherapy with immune checkpoint inhibitors(ICIs) has become the main option for treating cancers, including HCC. However, meta-analyses have shown that patients with NAFLD-related HCC are less likely to benefit from therapy based on ICIs alone. Conversely, the addition of an angiogenesis inhibitor showed better results regarding the objective response rate and progression-free survival. Adjunctive diagnostic and therapeutic strategies, such as the application of novel biomarkers and the modulation of gut microbiota, should be considered in the future to guide personalized medicine and improve the response to ICIs in patients with NAFLD-related HCC.

关键词： Hepatocellular carcinoma Immunotherapy liver cancer nonalcoholic fatty liver disease Metabolic dysfunction-associated fatty liver disease Obesity

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PNPLA3 rs738409 C>G Variant Influences the Association Between Visceral Fat and Significant Fibrosis in Biopsyproven nonalcoholic fatty liver disease

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Journal of Clinical and Translational Hepatology 2022年第3期10卷 439-448页

作者： Gang Li Liang-Jie Tang Pei-Wu Zhu Ou-Yang Huang Rafael SRios Kenneth IZheng Sui-Dan Chen Hong-Lei Ma Giovanni Targher Christopher DByrne Xiao-Yan Pan Ming-Hua Zheng NAFLD Research Center Department of Hepatologythe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiangChina Department of Laboratory Medicine the First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiangChina Department of Pathology the First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiangChina Section of Endocrinology Diabetes and MetabolismDepartment of MedicineUniversity and Azienda Ospedaliera Universitaria Integrata of VeronaVeronaItaly Southampton National Institute for Health Research Biomedical Research Centre University Hospital SouthamptonSouthampton General HospitalSouthamptonUK Department of Endocrinology the First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiangChina Institute of Hepatology Wenzhou Medical UniversityWenzhouZhejiangChina Key Laboratory of Diagnosis and Treatment for The Development of Chronic liver disease in Zhejiang Province WenzhouZhejiangChina

Background and Aims:Intra-abdominal visceral fat accumulation and patatin-like phospholipase domain containing 3(PNPLA3)rs738409 G/C gene polymorphism confer a greater susceptibility to nonalcoholic fatty liver disease(NAFLD).We examined whether the relationship between visceral fat accumulation and liver disease severity may be influenced by PNPLA3 rs738409 ***:The variant of PNPLA3 rs738409 was genotyped within 523 Han individuals with biopsy-confirmed *** fat area(VFA)was measured by bioelectrical *** liver fibrosis(SF),defined as stage F≥2 on histology,was the outcome measure of ***:The distribution of PNPLA3 genotypes was CC:27.5%,CG:48.2%,and GG:24.3%.Higher VFA was associated with greater risk of having SF(adjusted-odds ratio[OR]:1.03;95%confidence interval[CI]:1.02–1.04,p<0.05),independent of potential *** subjects with the same VFA level,the risk of SF was greater among carriers of the rs738409 G genotype than among those who did *** analysis showed that PNPLA3 rs738409 significantly influenced the association between VFA and *** remained significantly associated with SF only among the rs738409 G-allele carriers(adjusted-OR:1.05;95%CI:1.03–1.08 for the GG group;and adjusted-OR:1.03;95%CI:1.01–1.04 for the GC group).There was a significant interaction between VFA and PNPLA3 rs738409 genotype(Pinteraction=0.004).Conclusions:PNPLA3 rs738409 G allele has a moderate effect on the association between VFA and risk of SF in adult individuals with biopsy-proven *** of the PNPLA3 rs738409 G allele and VFA interact to increase risk of SF。

关键词： nonalcoholic fatty liver disease Significant fibrosis Visceral fat area Single nucleotide polymorphism Metabolic dysfunction-associated fatty liver disease

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Metabolic Disorders Combined with Noninvasive Tests to Screen Advanced Fibrosis in nonalcoholic fatty liver disease

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Journal of Clinical and Translational Hepatology 2021年第5期9卷 607-614页

作者： Yi-Wen Shi Fang-Ping He Jin-Jun Chen Hong Deng Jun-Ping Shi Cai-Yan Zhao Yu-Qiang Mi Zheng-Sheng Zou Yong-Jian Zhou Fu-Sheng Di Rui-Dan Zheng Qin Du Jia Shang Rui-Xu Yang Branko Popovic Bi-Hui Zhong Jian-Gao Fan Center for fatty liver Department of GastroenterologyXinhua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Key Lab of Pediatric Gastroenterology and NutritionShanghaiChina Department of Gastroenterology II The First Affiliated Hospital of Xinjiang Medical UniversityXinjiang Uygur Autonomous RegionsÜrümqiChina Hepatology Unit Department of Infectious DiseasesNanfang HospitalSouthern Medical UniversityGuangzhouChina Department of Infectious diseases the Third Affiliated HospitalSun Yat-Sen UniversityGuangzhouChina The Affiliated Hospital of Hangzhou Normal University HangzhouChina Department of Infectious disease The Third Hospital of Hebei Medical UniversityShijiazhuangChina Department of Infectious diseases Tianjin Second People’s HospitalTianjinChina Department of liver disease Chinese PLA General Hospitalthe Fifth Medical Center of Chinese PLA General HospitalBeijingChina Department of Gastroenterology and Hepatology Guangzhou First People’s HospitalSchool of MedicineSouth China University of TechnologyGuangzhouChina Department of Endocrinology and Metabolism The Third Central Hospital of TianjinTianjinChina Diagnosis and Treatment Center for liver diseases Zhengxing HospitalZhangzhouChina Department of Gastroenterology the Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina Department of Infectious diseases Henan Provincial Peoples’Hospital Zhengzhou ZhengzhouChina Sanofi-Aventis Deutschland GmbH FrankfurtGermany Department of Gastroenterology The First Affiliated HospitalSun Yat-Sen UniversityGuangzhouChina

Background and Aims:nonalcoholic fatty liver disease(NAFLD)is associated with metabolic *** study aimed to explore the role of metabolic disorders in screening advanced fibrosis in NAFLD ***:A total of 246 histologically-proven NAFLD patients were enrolled across 14 *** compared the severity of fibrosis in patients with different components of metabolic *** on standard noninvasive tests and metabolic disorders,we developed new algorithms to identify advanced ***:Metabolic syndrome(MetS)was frequent in NAFLD patients(133/246,54%).Patients with MetS had a higher proportion of significant fibrosis(p=0.014)and higher LSM values(9.2 kPa,vs.7.4 kPa,p=0.002)than those without *** with more metabolic disorders had higher fibrosis stages(p=0.017).Reduced highdensity lipoprotein cholesterol(odds ratio[OR]:2.241,95%confidence interval[CI]:1.004–5.002,p=0.049)and raised fasting glucose(OR:4.500,95%CI:2.083–9.725,pliver biopsy was reduced,especially in combination with the Fibrosis-4 score and metabolic disorders(36%to 17%,pliver biopsies.

关键词： nonalcoholic fatty liver disease liver fibrosis Metabolic syndrome Noninvasive measurement

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Apolipoprotein C3(-455T>C) polymorphism confers susceptibility to nonalcoholic fatty liver disease in the Southern Han Chinese population

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World Journal of Gastroenterology 2014年第38期20卷 14010-14017页

作者： Min-Rui Li Sheng-hong Zhang Kang Chao Xian-hua Liao Jia-yan yao Min-hu Chen Bi-hui Zhong Division of Gastroenterology The First Affiliated HospitalSun Yat-sen University

AIM:To investigate the relationship between Apolipoprotein C3(APOC3)(-455T>C) polymorphism and nonalcoholic fatty liver disease(NAFLD) in the Southern Chinese han ***:In this prospective case-control study,we recruited 300 NAFLD patients and 300 healthy controls to a cohort representing Southern Chinese han population at The First Affiliated Hospital,Sun Yat-sen University,from January to December 2012. Polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing were used to genotype the APOC3(-455T>C) ***:After adjusting for age,gender,and bodymass index,TC and CC genotypes were found to increase the susceptibility to NAFLD compared to the TT genotype,with adjusted odds ratios(ORs) of 1.77(95%CI:1.16-2.72) and 2.80(95%CI:1.64-4.79),respectively. Further stratification analysis indicated that carriers of the CC genotype was more susceptible to insulin resistance(IR) than those of the TT genotype,with an OR of 3.24(95%CI:1.52-6.92). The CC genotype also was associated with a significantly higher risk of hypertension,hypertriglyceridemia,and low levels of high-density lipoprotein cholesterol(hDL)(P C) polymorphism and obesity,impaired glucose tolerance,hyperuricemia,hypercholesterolemia,or high levels of low-density lipoprotein cholesterol(LDL)(P > 0.05).CONCLUSION:APOC3(-455T>C) genetic variation is involved in the susceptibility to developing NAFLD,IR,hypertension,hypertriglyceridemia,and low hDL in the Southern Chinese han population.

关键词： Apolipoprotein C3 nonalcoholic fatty liver disease Insulin resistance Metabolic disorder Polymor-phism

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Physical activity support or weight loss counseling for nonalcoholic fatty liver disease?

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World Journal of Gastroenterology 2014年第29期20卷 10128-10136页

作者： Luca Montesi Chiara Caselli Elena Centis Chiara Nuccitelli Simona Moscatiello Alessandro Suppini Giulio Marchesini Unit of Metabolic diseases and Clinical Dietetics "Alma Mater Studiorum" University S. Orsola-Malpighi Hospital

AIM: To determine the clinical effectiveness of intense psychological support to physical activity (PA) in nonalcoholic fatty liver disease (NAFLD), compared with cognitive-behavioral treatment (CBT).

关键词： nonalcoholic fatty liver disease Behavior treatment Physical activity Physical fitness Weight loss liver fat liver enzymes

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Dietary habits and behaviors associated with nonalcoholic fatty liver disease

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World Journal of Gastroenterology 2014年第7期20卷 1756-1767页

作者： Kenichiro Yasutake Motoyuki Kohjima Kazuhiro Kotoh Manabu Nakashima Makoto Nakamuta Munechika Enjoji Department of Health and Nutrition Sciences Faculty of Health and Social Welfare SciencesNishikyushu UniversityKanzaki 842-8585Japan Department of Gastroenterology and Clinical Research Center Kyushu Medical CenterNational Hospital OrganizationFukuoka 810-8563Japan Department of Hepatology and Pancreatology Kyushu University HospitalFukuoka 812-8582Japan Faculty of Pharmaceutical Sciences Fukuoka UniversityFukuoka 814-0180Japan Health Care Center Fukuoka UniversityFukuoka 814-0180Japan

nonalcoholic fatty liver disease(NAFLD)is one of the most frequent causes of health problems in Western(industrialized)***,the incidence of infantile NAFLD is increasing,with some of these patients progressing to nonalcoholic *** trends depend on dietary habits and *** particular,overeating and its associated obesity affect the development of *** problems in patients with NAFLD include excess intake of energy,carbohydrates,and lipids,and shortages of polyunsaturated fatty acids,vitamins,and *** nutritional therapeutic approaches are required for prophylaxis and treatment of NAFLD,continuous nutrition therapy is difficult for many patients because of their dietary habits and lifestyle,and because the motivation for treatment differs among ***,it is necessary to assess the nutritional background and to identify nutritional problems in each patient with *** assessing dietary habits,it is important to individually evaluate those that are consumed excessively or insufficiently,as well as inappropriate eating *** nutrition therapy requires patient education,based on assessments of individual nutrients,and continuing the *** this article,we update knowledge about NAFLD,review the important aspects of nutritional assessment targeting treatment success,and present some concrete nutritional care plans which can be applied generally.

关键词： nonalcoholic fatty liver disease Nutritional therapy Carbohydrates fatty acids Cholesterol

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Ursodeoxycholic acid as a means of preventing atherosclerosis,steatosis and liver fibrosis in patients with nonalcoholic fatty liver disease

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World Journal of Gastroenterology 2021年第10期27卷 959-975页

作者： Maria Nadinskaia Marina Maevskaya Vladimir Ivashkin Khava Kodzoeva Irina Pirogova Evgeny Chesnokov Alexander Nersesov Jamilya Kaibullayeva Akzhan Konysbekova Aigul Raissova Feruza Khamrabaeva Elena Zueva Department of Propaedeutics of Internal diseases Gastroenterology and HepatologySechenov First Moscow State Medical University(Sechenov University)Moscow 119991Russia Vasilenko Clinic of Internal diseases Propedeutics Gastroenterology and HepatologyUniversity Clinical Hospital№2Sechenov First Moscow State Medical University(Sechenov University)Moscow 119991Russia LLC MC“Lotus” Center for Gastroenterology and HepatologyChelyabinsk 454092Russia Department of Hospital Therapy with the Course of Endocrinology and Clinical Pharmacology Tyumen State Medical UniversityTyumen 625003Russia Department of Gastroenterology S.Asfendiyarov Kazakh National Medical UniversityAlmaty 050000Kazakhstan Functional and Ultrasound Diagnostics Scientific and Research Institute of Cardiology and Internal DiseasesAlmaty 050000Kazakhstan Department of Internal diseases Scientific and Research Institute of Cardiology and Internal DiseasesAlmaty 050000Kazakhstan Faculty of Therapy Tashkent Institute of Advanced Medical StudiesTashkent 100007Uzbekistan Department of Therapy№1 with Training General Practitioners Tashkent Medical AcademyTashkent 100109Uzbekistan

BACKGROUND Atherosclerotic cardiovascular disease(ASCVD)is the leading cause of mortality in patients with nonalcoholic fatty liver disease(NAFLD).Weight loss is a key factor for successful NAFLD and CVD *** acid(UDCA),which is one of the first-line therapeutic agents for treatment of NAFLD,is reported to have a beneficial effect on dyslipidemia and ASCVD risk because of antioxidant *** To evaluate the effects of 6 mo of UDCA treatment on hepatic function tests,lipid profile,hepatic steatosis and fibrosis,atherogenesis,and ASCVD risk in men and women with NAFLD,as well as to assess the impact of>5%weight reduction on these *** An open-label,multicenter,international noncomparative trial was carried out at primary health care settings and included 174 patients with ultrasound-diagnosed NAFLD who received 15 mg/kg/d UDCA for 6 mo and were prescribed lifestyle modification with diet and *** efficacy criteria were liver enzymes,lipid profile,fatty liver index(FLI),noninvasive liver fibrosis tests(nonalcoholic fatty liver disease fibrosis score and liver fibrosis index),carotid intima-media thickness(CIMT),and ASCVD risk *** test statistical hypotheses,the Wilcoxon test,paired t-test,Fisher’s exact test,and Pearson's chi-squared test were *** The alanine aminotransferase(ALT)level changed by-14.1 U/L(-31.0;-5.3)from baseline to 3 mo and by-6.5 U/L(-14.0;0.1)from 3 to 6 *** magnitude of ALT,aspartate transaminase,and glutamyltransferase decrease was greater during the first 3 mo of treatment compared to the subsequent 3 mo(Pnonalcoholic fatty liver disease

关键词： Ursodeoxycholic acid nonalcoholic fatty liver disease liver function tests fatty liver index Carotid intima-media thickness Atherosclerotic cardiovascular disease

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Impact of continuous positive airway pressure therapy for nonalcoholic fatty liver disease in patients with obstructive sleep apnea

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World Journal of Clinical Cases 2021年第19期9卷 5112-5125页

作者： Haruka Hirono Kazuhiko Watanabe Katsuhiko Hasegawa Masaki Kohno Shuji Terai Shogo Ohkoshi Department of Internal Medicine The Nippon Dental University School of Life Dentistry at NiigataNiigata 951-8580Japan The Center for Dental Sleep Medicine The Nippon Dental University Niigata HospitalNiigata 951-8580Japan Division of Gastroenterology and Hepatology Graduate School of Medical and Dental SciencesNiigata UniversityNiigata 951-8510Japan

BACKGROUND Obstructive sleep apnea(OSA)has been suggested as an independent risk factor for nonalcoholic fatty liver disease(NAFLD),and continuous positive airway pressure(CPAP)is the first-line therapy for *** To clarify the efficacy of effective CPAP therapy on NAFLD of OSA patients by serum markers and transient elastography(TE)using FibroScan®(Echosens,Paris,France).METHODS We prospectively enrolled 123 consecutive patients with OSA who met the indications for *** fibrosis and steatosis were assessed using *** and after 6 mo of CPAP therapy,serum markers and TE were assessed for all *** mean usage rate of CPAP therapy for 6 mo was arbitrarily calculated in each patient and expressed as“mean compliance index”(m-CI).RESULTS In 50 OSA patients with NAFLD,both aspartate aminotransferase(AST)and alanine aminotransferase(ALT)levels were significantly decreased after 6 mo of CPAP *** analysis showed that decreased body weight(BW),decreased body mass index(BMI),decreased AST level,decreased hemoglobin A1c,and high m-CI were significantly related with improved ALT *** multivariate regression model adjusted for quantities of BW change during 6 mo of CPAP therapy,high m-CI tended to improve ALT level(P=0.051).All 17 OSA patients with NAFLD,high m-CI and no BMI changes showed significant improvements in AST and ALT ***,no significant changes in TE data or serum fibrosis markers were *** Some NAFLD could be associated with chronic intermittent hypoxia due to OSA independent of BW *** those cases,adequate reoxygenation from effective CPAP therapy may improve NAFLD.

关键词： nonalcoholic fatty liver disease Obstructive sleep apnea Continuous positive airway pressure Chronic intermittent hypoxia Transient elastography

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PPARGC1A rs8192678 G>A polymorphism affects the severity of hepatic histological features and nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease

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World Journal of Gastroenterology 2021年第25期27卷 3863-3876页

作者： Rui-Nan Zhang Feng Shen Qin Pan Hai-Xia Cao Guang-Yu Chen Jian-Gao Fan Center for fatty liver Department of GastroenterologyXinhua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200092China Clinical Epidemiology Research Center Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200092China Center for fatty liver Department of GastroenterologyXinhua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Key Lab of Pediatric Gastroenterology and NutritionShanghai 200092China

BACKGROUND The association between PPARGC1A rs8192678 and nonalcoholic fatty liver disease(NAFLD)requires further *** addition,it is still unknown whether PPARGC1A rs8192678 is associated with hepatic histological features in NAFLD in the Chinese *** To investigate the interaction between PPARGC1A rs8192678 and nonalcoholic steatohepatitis(NASH),and whether this polymorphism is associated with hepatic histological *** Fifty-nine patients with liver biopsy-proven NAFLD and 93 healthy controls were recruited to a cohort representing the Chinese Han *** SAF(steatosis,activity,and fibrosis)scoring system was used for hepatic histopathological *** polymorphisms of PPARGC1A rs8192678 and patatin-like phospholipase domain-containing protein 3(PNPLA3)rs738409 were *** intrahepatic mRNA expression of PPARGC1A was evaluated by real-time polymerase chain *** Thirty-seven patients with NAFLD had NASH,of which 12 were *** PPARGC1A rs8192678 risk A allele(carrying GA and AA genotypes)had the lowest P value in the dominant model;the odds ratio(OR)for NAFLD was 2.321[95%confidence interval(CI):1.121-4.806].After adjusting for age,sex,and the PNPLA3 rs738409 risk G allele,the PPARGC1A rs8192678 A allele was a risk factor for NAFLD(OR 2.202,95%CI:1.030-4.705,P=0.042).The genetic analysis showed that patients with NAFLD,moderate-to-severe steatosis(S2-3),and Activity 2-4(A≥2)were more likely to carry A in PPARGC1A rs8192678(OR 5.000,95%CI:1.343-18.620,P=0.012;and OR 4.071,95%CI:1.076-15.402,P=0.031).The multivariate logistic regression analysis showed that PPARGC1A rs8192678 risk A allele was also independently associated with S2-3,A≥2,and NASH(OR 6.190,95%CI:1.508-25.410,P=0.011;OR 4.506,95%CI 1.070-18.978,P=0.040;and OR 6.337,95%CI:1.135-35.392,P=0.035,respectively)after adjusting for age,sex,body mass index,and PNPLA3 rs738409 risk G *** results also showed that this polymorphism was as

关键词： nonalcoholic fatty liver disease nonalcoholic steatohepatitis PPARGC1A rs8192678 polymorphism Steatosis Activity

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