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The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD)

Published on Aug 1, 2016in Metabolism-clinical and Experimental6.51
· DOI :10.1016/j.metabol.2015.12.012
Elena Buzzetti4
Estimated H-index: 4
(Royal Free Hospital),
Massimo Pinzani77
Estimated H-index: 77
(Royal Free Hospital),
Emmanuel Tsochatzis29
Estimated H-index: 29
(Royal Free Hospital)
Cite
Abstract
Abstract Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and represents a growing challenge in terms of prevention and treatment. Despite its high prevalence, only a small minority of affected patients develops inflammation and subsequently fibrosis and chronic liver disease, while most of them only exhibit simple steatosis. In this context, the full understanding of the mechanisms underlying the development of NAFLD and non-alcoholic steatohepatitis (NASH) is of extreme importance; despite advances in this field, knowledge on the pathogenesis of NAFLD is still incomplete. The ‘two-hit’ hypothesis is now obsolete, as it is inadequate to explain the several molecular and metabolic changes that take place in NAFLD. The “multiple hit” hypothesis considers multiple insults acting together on genetically predisposed subjects to induce NAFLD and provides a more accurate explanation of NAFLD pathogenesis. Such hits include insulin resistance, hormones secreted from the adipose tissue, nutritional factors, gut microbiota and genetic and epigenetic factors. In this article, we review the factors that form this hypothesis.
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  • References (148)
  • Citations (282)
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References148
Newest
Published on Apr 1, 2016in European Journal of Nutrition4.45
Giridhar Kanuri14
Estimated H-index: 14
(FSU: University of Jena),
Marianne Landmann6
Estimated H-index: 6
(FSU: University of Jena)
+ 6 AuthorsIna Bergheim31
Estimated H-index: 31
(FSU: University of Jena)
Purpose Using ob/ob mice as a model of non-alcoholic fatty liver disease (NAFLD), we investigated the effect of moderate alcohol intake on the development of NAFLD and molecular mechanisms involved.
Published on Sep 1, 2015in Gastroenterology19.23
Johannie Du Plessis5
Estimated H-index: 5
(University of Pretoria),
J. van Pelt27
Estimated H-index: 27
(Katholieke Universiteit Leuven)
+ 17 AuthorsSimon Nayler13
Estimated H-index: 13
(University of the Witwatersrand)
Schalk van der Merwe, Chantal Mathieu, Frederik Nevens, David Cassiman, and Sven Francque are recipients of the Flanders fund for scientific research (FWO klinisch mandaat), and Hannelie Korf is a recipient of the FWO postdoctoral mandate. Research at the Department of Endocrinology, Diabetology and Metabolism and the Department of Gastroenterology and Hepatology of the Antwerp University Hospital (Belgium) was supported by the European Union: FP6 (HEPADIP contract LSHM-CT-2005-018734) and FP7-H...
Published on Sep 1, 2015in Clinical Biochemistry2.43
Irina A. Kirpich16
Estimated H-index: 16
(University of Louisville),
Luis Marsano18
Estimated H-index: 18
(University of Louisville),
Craig J. McClain63
Estimated H-index: 63
(University of Louisville)
Abstract Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of diseases involving hepatic fat accumulation, inflammation with the potential progression to fibrosis and cirrhosis over time. NAFLD is often associated with obesity, insulin resistance, and diabetes. The interactions between the liver and the gut, the so-called “gut–liver axis”, play a critical role in NAFLD onset and progression. Compelling evidence links the gut microbiome, intestinal barrier integrity, and NAFLD. The d...
Published on Aug 1, 2015in Gastroenterology19.23
Paul Angulo69
Estimated H-index: 69
(UK: University of Kentucky),
E KleinerDavid83
Estimated H-index: 83
+ 9 AuthorsAlisha C. Stahler3
Estimated H-index: 3
(Mayo Clinic)
Background & Aims Histologic analysis of liver biopsy specimens allows for grading and staging of nonalcoholic fatty liver disease (NAFLD). We performed a longitudinal study to investigate the long-term prognostic relevance of histologic features for patients with NAFLD. Methods We performed a retrospective analysis of 619 patients diagnosed with NAFLD from 1975 through 2005 at medical centers in the United States, Europe, and Thailand. Patients underwent laboratory and biopsy analyses, and were...
Published on Aug 1, 2015in Journal of Hepatology18.95
Jiantao Ma9
Estimated H-index: 9
(Tufts University),
Caroline S. Fox124
Estimated H-index: 124
(Harvard University)
+ 5 AuthorsNicola M. McKeown36
Estimated H-index: 36
(Tufts University)
Background & Aims Non-alcoholic fatty liver disease affects ∼30% of US adults, yet the role of sugar-sweetened beverages and diet soda on these diseases remains unknown. We examined the cross-sectional association between intake of sugar-sweetened beverages or diet soda and fatty liver disease in participants of the Framingham Offspring and Third Generation cohorts. Methods Fatty liver disease was defined using liver attenuation measurements generated from computed tomography in 2634 participant...
Published on Aug 1, 2015in Scientific Reports4.01
Renfan Xu5
Estimated H-index: 5
,
Anyu Tao5
Estimated H-index: 5
+ 2 AuthorsGuangzhi Chen10
Estimated H-index: 10
We conducted a meta-analysis to assess the association between patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 polymorphism and nonalcoholic fatty liver disease (NAFLD) and its subtypes simple steatosis(SS) and nonalcoholic steatohepatitis (NASH). The study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using fixed-effects or random-effects models, with assessment for heterogeneity and publication bias. Twenty-three case-control studies involving 6...
Published on May 1, 2015in The Journal of Clinical Endocrinology and Metabolism5.61
Rosellina Margherita Mancina16
Estimated H-index: 16
(University of Gothenburg),
Niina Matikainen16
Estimated H-index: 16
(HYKS: Helsinki University Central Hospital)
+ 10 AuthorsLuca Valenti48
Estimated H-index: 48
Context: Nonalcoholic fatty liver disease (NAFLD) is an emerging epidemic disease characterized by increased hepatic fat, due to an imbalance between synthesis and removal of hepatic lipids. In particular, increased hepatic de novo lipogenesis (DNL) is a key feature associated with NAFLD. The genetic variations I148M in PNPLA3 and E167K in TM6SF2 confer susceptibility to NAFLD. Objective: Here we aimed to investigate the contribution of DNL to liver fat accumulation in the PNPLA3 I148M or TM6SF2...
Published on Apr 1, 2015in Nutrition & Diabetes3.10
Alastair Duly3
Estimated H-index: 3
,
B Alani1
Estimated H-index: 1
+ 4 AuthorsDevanshi Seth18
Estimated H-index: 18
Abstract Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are highly prevalent liver diseases that may coexist and contribute significantly to liver disease-related mortality. Obesity is a common underlying risk factor for both disorders. There has been little research investigating the combined effects of high fat diet (HFD) and alcohol. Current mouse models of alcohol- or fat-rich diet alone do not lead to severe liver injury. There is a need to develop animal models...
Published on Apr 1, 2015in Journal of Hepatology18.95
Akio Moriya7
Estimated H-index: 7
,
Yoshiaki Iwasaki28
Estimated H-index: 28
(Okayama University)
+ 5 AuthorsKazuhide Yamamoto39
Estimated H-index: 39
(Okayama University)
Background & Aims Roles of alcohol consumption in non-alcoholic fatty liver disease are still controversial, although several cross-sectional studies have suggested the beneficial effect of light to moderate drinking on fatty liver. We analyzed the longitudinal relationship between drinking pattern and fatty liver. Methods We included 5297 Japanese individuals (3773 men and 1524 women) who underwent a baseline study in 2003 and follow-up at least once from 2004 to 2006. Generalized estimating eq...
Published on Feb 1, 2015in Hepatology14.97
Paola Dongiovanni38
Estimated H-index: 38
,
Salvatore Petta38
Estimated H-index: 38
+ 25 AuthorsStefania Grimaudo29
Estimated H-index: 29
Excess hepatic storage of triglycerides is considered a benign condition, but nonalcoholic steatohepatitis (NASH) may progress to fibrosis and promote atherosclerosis. Carriers of the TM6SF2 E167K variant have fatty liver as a result of reduced secretion of very-low-density lipoproteins (VLDLs). As a result, they have lower circulating lipids and reduced risk of myocardial infarction. In this study, we aimed to assess whether TM6SF2 E167K affects liver damage and cardiovascular outcomes in subje...
Cited By282
Newest
Published on Dec 1, 2019in Clinical Epigenetics
Matthew C. Sinton (BHF: British Heart Foundation), David C. Hay28
Estimated H-index: 28
(Edin.: University of Edinburgh),
Amanda J. Drake25
Estimated H-index: 25
(BHF: British Heart Foundation)
Non-alcoholic fatty liver disease (NAFLD) is estimated to affect 24% of the global adult population. NAFLD is a major risk factor for the development of cirrhosis and hepatocellular carcinoma, as well as being strongly associated with type 2 diabetes and cardiovascular disease. It has been proposed that up to 88% of obese adults have NAFLD, and with global obesity rates increasing, this disease is set to become even more prevalent. Despite intense research in this field, the molecular processes ...
Published on Jan 18, 2019in Scientific Reports4.01
Eri Kawashita9
Estimated H-index: 9
(Kyoto Pharmaceutical University),
Keiichi Ishihara16
Estimated H-index: 16
(Kyoto Pharmaceutical University)
+ 2 AuthorsSatoshi Akiba22
Estimated H-index: 22
(Kyoto Pharmaceutical University)
C57BL/6J (BL6J) and C57BL/6N (BL6N) inbred substrains are most widely used to understand the pathological roles of target molecules in a variety of diseases, including non-alcoholic steatohepatitis (NASH), based on transgenic mouse technologies. There are notable differences in the metabolic phenotypes, including glucose tolerance, between the BL6J and BL6N substrains, but the phenotypic differences in NASH are still unknown. We performed a comparative analysis of the two mouse substrains to ide...
Published in BMC Gastroenterology2.25
Saeede Saadati1
Estimated H-index: 1
(Shahid Beheshti University of Medical Sciences and Health Services),
Amir Sadeghi3
Estimated H-index: 3
(Shahid Beheshti University of Medical Sciences and Health Services)
+ -3 AuthorsAzita Hekmatdoost21
Estimated H-index: 21
(Shahid Beheshti University of Medical Sciences and Health Services)
Background The aim of the present study was to evaluate the effects of curcumin supplementation on inflammatory indices, and hepatic features in patients with non-alcoholic fatty liver disease (NAFLD).
Lu Han2
Estimated H-index: 2
(Stanford University),
Stefanie Bittner4
Estimated H-index: 4
(VA Palo Alto Healthcare System)
+ -3 AuthorsSalman Azhar43
Estimated H-index: 43
(Stanford University)
Abstract Creosote bush (Larrea tridentata)-derived nordihydroguaiaretic acid (NDGA) was shown to have profound effects on the core components of metabolic syndrome. This study investigated the in vivo potential of NDGA for prevention or attenuation of the pathophysiologic abnormalities of NASH. A novel dietary NASH model with feeding C57BL/6J mice with a high trans-fat, high cholesterol and high fructose (HTF) diet, was used. The HTF diet fed mice exhibited obesity, insulin resistance, hepatic s...
Published on Mar 11, 2019in Scientific Reports4.01
Xian-E Peng6
Estimated H-index: 6
(Fujian Medical University),
Shang-Hua Xu (Fujian Medical University)+ 3 AuthorsXu Lin12
Estimated H-index: 12
(Fujian Medical University)
Iron is an essential mineral required for most forms of life. However, very little is known in relation to the different forms of dietary iron on the development of NAFLD. The aims of this study were to investigate the effects of iron intake from different food types on risk of NAFLD and whether this effect may be modified by other factors. We conducted a hospital-based case–control study including 1,273 NAFLD cases and 1,273 gender and age-matched controls. We conducted in-person interviews whi...
Published in BMC Research Notes
Matthew B. Pickich (Edward Via College of Osteopathic Medicine), Mark W. Hargrove (Edward Via College of Osteopathic Medicine)+ -3 AuthorsJeffrey S. Martin16
Estimated H-index: 16
(UM: University of Michigan)
We recently reported that curcumin supplementation in a metabolically (i.e., Western diet [WD]) and chemically (i.e., CCl4) induced female rat model of non-alcoholic steatohepatitis (NASH) was associated with lower liver pathology scores and molecular markers of inflammation. This occurred when curcumin was given during induction of disease (preventative arm; 8-week WD with or without curcumin [8WD + C vs. 8WD]) as well as when given after disease development (treatment arm; 12-week WD with or w...
R. Chris Skinner (WVU: West Virginia University), Derek C. Warren (WVU: West Virginia University)+ -3 AuthorsJanet C. Tou19
Estimated H-index: 19
(WVU: West Virginia University)
Abstract Non-alcoholic steatohepatitis (NASH) is diet-driven and characterized by inflammation and alterations in liver-adipose fatty acid transport. Diet modification is the main treatment for NASH, with high antioxidant diets suggested. Apple pomace, an antioxidant-rich apple processing “waste” byproduct, has potential as a functional food in alleviating NASH. To investigate apple pomace and NASH, growing female Sprague-Dawley rats consumed one of four diets for 8 weeks: AIN-93G, AIN-93G/10% g...
Published on Oct 1, 2019in Journal of Hazardous Materials7.65
Chunxue Yang3
Estimated H-index: 3
(Hong Kong Baptist University),
Lin Zhu1
Estimated H-index: 1
(Hong Kong Baptist University)
+ 4 AuthorsZongwei Cai49
Estimated H-index: 49
(Hong Kong Baptist University)
Abstract Exposure to polybrominated diphenyl ethers (PBDEs), is closely associated with the occurrence of obesity and non-alcoholic fatty liver disease (NAFLD), yet their pathological effects and underlying mechanisms remain unclear. To examine the role of 2, 2′, 4, 4′-tetrabromodiphenyl ether (BDE-47) in the progression of NAFLD under obese condition, male C57BL/6 J mice were fed with diet interaction for 15 weeks and subcutaneously injected with BDE-47 (7 mg/kg or 70 mg/kg) or the vehicle week...
Published on Sep 1, 2019in International Immunopharmacology3.36
Dongzhi Chen2
Estimated H-index: 2
(Hebei University),
Xiang Gao (Hebei University)+ 5 AuthorsMing Meng4
Estimated H-index: 4
(Hebei University)
Abstract The existence of association between the subpopulation of iNKT cells with different functions and nonalcoholic fatty liver disease has not been confirmed. To investigative the role of iNKT cells in the pathogenesis of nonalcoholic fatty liver disease, we established a non-alcoholic fatty liver model by feeding C57BL/6J mice for 12 weeks with a high-fat diet and injecting α-GalCer through different routes to activate hepatic iNKT cells. The liver of the mice fed a high-fat diet (HFD) had...