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Signal Transduction and Targeted Therapy Aug 2022Non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH) has become the leading cause of liver disease worldwide. NASH, an advanced form of NAFL, can be... (Review)
Review
Non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH) has become the leading cause of liver disease worldwide. NASH, an advanced form of NAFL, can be progressive and more susceptible to developing cirrhosis and hepatocellular carcinoma. Currently, lifestyle interventions are the most essential and effective strategies for preventing and controlling NAFL without the development of fibrosis. While there are still limited appropriate drugs specifically to treat NAFL/NASH, growing progress is being seen in elucidating the pathogenesis and identifying therapeutic targets. In this review, we discussed recent developments in etiology and prospective therapeutic targets, as well as pharmacological candidates in pre/clinical trials and patents, with a focus on diabetes, hepatic lipid metabolism, inflammation, and fibrosis. Importantly, growing evidence elucidates that the disruption of the gut-liver axis and microbe-derived metabolites drive the pathogenesis of NAFL/NASH. Extracellular vesicles (EVs) act as a signaling mediator, resulting in lipid accumulation, macrophage and hepatic stellate cell activation, further promoting inflammation and liver fibrosis progression during the development of NAFL/NASH. Targeting gut microbiota or EVs may serve as new strategies for the treatment of NAFL/NASH. Finally, other mechanisms, such as cell therapy and genetic approaches, also have enormous therapeutic potential. Incorporating drugs with different mechanisms and personalized medicine may improve the efficacy to better benefit patients with NAFL/NASH.
Topics: Fibrosis; Humans; Inflammation; Liver Cirrhosis; Liver Neoplasms; Non-alcoholic Fatty Liver Disease; Signal Transduction
PubMed: 35963848
DOI: 10.1038/s41392-022-01119-3 -
Nature Reviews. Immunology Jul 2022Non-alcoholic fatty liver disease (NAFLD) includes a range of hepatic manifestations, starting with liver steatosis and potentially evolving towards non-alcoholic... (Review)
Review
Non-alcoholic fatty liver disease (NAFLD) includes a range of hepatic manifestations, starting with liver steatosis and potentially evolving towards non-alcoholic steatohepatitis (NASH), cirrhosis or even hepatocellular carcinoma. NAFLD is a major health burden, and its incidence is increasing worldwide. Although it is primarily a disease of disturbed metabolism, NAFLD involves several immune cell-mediated inflammatory processes, particularly when reaching the stage of NASH, at which point inflammation becomes integral to the progression of the disease. The hepatic immune cell landscape is diverse at steady state and it further evolves during NASH with direct consequences for disease severity. In this Review, we discuss current concepts related to the role of immune cells in the onset and progression of NASH. A better understanding of the mechanisms by which immune cells contribute to NASH pathogenesis should aid the design of innovative drugs to target NASH, for which current therapeutic options are limited.
Topics: Humans; Inflammation; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease; Severity of Illness Index
PubMed: 34741169
DOI: 10.1038/s41577-021-00639-3 -
Journal of Hepatology Jul 2020The exclusion of other chronic liver diseases including "excess" alcohol intake has until now been necessary to establish a diagnosis of metabolic dysfunction-associated... (Review)
Review
The exclusion of other chronic liver diseases including "excess" alcohol intake has until now been necessary to establish a diagnosis of metabolic dysfunction-associated fatty liver disease (MAFLD). However, given our current understanding of the pathogenesis of MAFLD and its rising prevalence, "positive criteria" to diagnose the disease are required. In this work, a panel of international experts from 22 countries propose a new definition for the diagnosis of MAFLD that is both comprehensive and simple, and is independent of other liver diseases. The criteria are based on evidence of hepatic steatosis, in addition to one of the following three criteria, namely overweight/obesity, presence of type 2 diabetes mellitus, or evidence of metabolic dysregulation. We propose that disease assessment and stratification of severity should extend beyond a simple dichotomous classification to steatohepatitis vs. non-steatohepatitis. The group also suggests a set of criteria to define MAFLD-associated cirrhosis and proposes a conceptual framework to consider other causes of fatty liver disease. Finally, we bring clarity to the distinction between diagnostic criteria and inclusion criteria for research studies and clinical trials. Reaching consensus on the criteria for MAFLD will help unify the terminology (e.g. for ICD-coding), enhance the legitimacy of clinical practice and clinical trials, improve clinical care and move the clinical and scientific field of liver research forward.
Topics: Causality; Consensus; Diabetes Mellitus, Type 2; Disease Progression; Fatty Liver; Humans; Liver Cirrhosis; Metabolic Diseases; Obesity; Terminology as Topic
PubMed: 32278004
DOI: 10.1016/j.jhep.2020.03.039 -
Hepatology Communications Jan 2022The rising prevalence of nonalcoholic fatty liver disease (NAFLD) and NAFLD-related cirrhosis in the United States and globally highlights the need to better understand... (Review)
Review
The rising prevalence of nonalcoholic fatty liver disease (NAFLD) and NAFLD-related cirrhosis in the United States and globally highlights the need to better understand the mechanisms causing progression of hepatic steatosis to fibrosing steatohepatitis and cirrhosis in a small proportion of patients with NAFLD. Accumulating evidence suggests that lipotoxicity mediated by hepatic free cholesterol (FC) overload is a mechanistic driver for necroinflammation and fibrosis, characteristic of nonalcoholic steatohepatitis (NASH), in many animal models and also in some patients with NASH. Diet, lifestyle, obesity, key genetic polymorphisms, and hyperinsulinemia secondary to insulin resistance are pivotal drivers leading to aberrant cholesterol signaling, which leads to accumulation of FC within hepatocytes. FC overload in hepatocytes can lead to ER stress, mitochondrial dysfunction, development of toxic oxysterols, and cholesterol crystallization in lipid droplets, which in turn lead to hepatocyte apoptosis, necrosis, or pyroptosis. Activation of Kupffer cells and hepatic stellate cells by hepatocyte signaling and cholesterol loading contributes to this inflammation and leads to hepatic fibrosis. Cholesterol accumulation in hepatocytes can be readily prevented or reversed by statins. Observational studies suggest that use of statins in NASH not only decreases the substantially increased cardiovascular risk, but may ameliorate liver pathology. Conclusion: Hepatic FC loading may result in cholesterol-associated steatohepatitis and play an important role in the development and progression of NASH. Statins appear to provide significant benefit in preventing progression to NASH and NASH-cirrhosis. Randomized controlled trials are needed to demonstrate whether statins or statin/ezetimibe combination can effectively reverse steatohepatitis and liver fibrosis in patients with NASH.
Topics: Animals; Anticholesteremic Agents; Cholesterol; Cholesterol, Dietary; Ezetimibe; Fatty Liver; Homeostasis; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Non-alcoholic Fatty Liver Disease; Risk Factors
PubMed: 34558856
DOI: 10.1002/hep4.1801 -
Drug Metabolism Reviews May 2017Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disorders. It is defined by the presence of steatosis in more than 5% of hepatocytes with little or no... (Review)
Review
Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disorders. It is defined by the presence of steatosis in more than 5% of hepatocytes with little or no alcohol consumption. Insulin resistance, the metabolic syndrome or type 2 diabetes and genetic variants of PNPLA3 or TM6SF2 seem to play a role in the pathogenesis of NAFLD. The pathological progression of NAFLD follows tentatively a "three-hit" process namely steatosis, lipotoxicity and inflammation. The presence of steatosis, oxidative stress and inflammatory mediators like TNF-α and IL-6 has been implicated in the alterations of nuclear factors such as CAR, PXR, PPAR-α in NAFLD. These factors may result in altered expression and activity of drug metabolizing enzymes (DMEs) or transporters. Existing evidence suggests that the effect of NAFLD on CYP3A4, CYP2E1 and MRP3 is more consistent across rodent and human studies. CYP3A4 activity is down-regulated in NASH whereas the activity of CYP2E1 and the efflux transporter MRP3 is up-regulated. However, it is not clear how the majority of CYPs, UGTs, SULTs and transporters are influenced by NAFLD either in vivo or in vitro. The alterations associated with NAFLD could be a potential source of drug variability in patients and could have serious implications for the safety and efficacy of xenobiotics. In this review, we summarize the effects of NAFLD on the regulation, expression and activity of major DMEs and transporters. We also discuss the potential mechanisms underlying these alterations.
Topics: Animals; Humans; Non-alcoholic Fatty Liver Disease; Pharmacokinetics
PubMed: 28303724
DOI: 10.1080/03602532.2017.1293683 -
Cell Metabolism Aug 2019Human organoid systems recapitulate in vivo organ architecture yet fail to capture complex pathologies such as inflammation and fibrosis. Here, using 11 different...
Human organoid systems recapitulate in vivo organ architecture yet fail to capture complex pathologies such as inflammation and fibrosis. Here, using 11 different healthy and diseased pluripotent stem cell lines, we developed a reproducible method to derive multi-cellular human liver organoids composed of hepatocyte-, stellate-, and Kupffer-like cells that exhibit transcriptomic resemblance to in vivo-derived tissues. Under free fatty acid treatment, organoids, but not reaggregated cocultured spheroids, recapitulated key features of steatohepatitis, including steatosis, inflammation, and fibrosis phenotypes in a successive manner. Interestingly, an organoid-level biophysical readout with atomic force microscopy demonstrated that organoid stiffening reflects the fibrosis severity. Furthermore, organoids from patients with genetic dysfunction of lysosomal acid lipase phenocopied severe steatohepatitis, rescued by FXR agonism-mediated reactive oxygen species suppression. The presented key methodology and preliminary results offer a new approach for studying a personalized basis for inflammation and fibrosis in humans, thus facilitating the discovery of effective treatments.
Topics: Cells, Cultured; Fatty Liver; Humans; Male; Models, Biological; Organoids; Pluripotent Stem Cells
PubMed: 31155493
DOI: 10.1016/j.cmet.2019.05.007 -
Nutrients Sep 2017Nonalcoholic fatty liver disease (NAFLD) constitutes a major health concern with the increasing incidence of obesity and diabetes in many Western countries, reaching a... (Review)
Review
Nonalcoholic fatty liver disease (NAFLD) constitutes a major health concern with the increasing incidence of obesity and diabetes in many Western countries, reaching a prevalence of up to 30% in the general population. Animal models have played a vital role in elucidating the pathophysiological mechanisms of NAFLD and continue to do so. A myriad of different models exists, each with its advantages and disadvantages. This review presents a brief overview of these models with a particular focus on the basic mechanisms and physical, biochemical and histological phenotype. Both nutritional and chemically induced, as well as genetic models are examined, including models combining different approaches.
Topics: Animals; Disease Models, Animal; Disease Progression; Female; Humans; Lipid Metabolism; Liver; Male; Mice, Transgenic; Non-alcoholic Fatty Liver Disease; Rabbits; Rats; Sex Factors; Species Specificity; Time Factors
PubMed: 28953222
DOI: 10.3390/nu9101072 -
Gastroenterology Clinics of North... Dec 2016Nonalcoholic fatty liver disease (NAFLD) is an important cause of morbidity and mortality worldwide and is rapidly becoming the leading cause of end-stage liver disease... (Review)
Review
Nonalcoholic fatty liver disease (NAFLD) is an important cause of morbidity and mortality worldwide and is rapidly becoming the leading cause of end-stage liver disease and liver transplant. With a prevalence of 30% in the United States, it has reached epidemic proportions. The clinical syndrome of NAFLD spans from bland steatosis to steatohepatitis, which can progress to fibrosis and cirrhosis. The pathogenesis includes the roles of hormones, nutritional and intestinal dysbiosis, insulin resistance, lipotoxicity, hepatic inflammation, and genes. Noninvasive testing and liver biopsy indications are reviewed. Approved and investigational therapies for NAFLD and nonalcoholic steatohepatitis are outlined in this article.
Topics: Combined Modality Therapy; Gastrointestinal Agents; Humans; Non-alcoholic Fatty Liver Disease; Risk Factors; Weight Reduction Programs
PubMed: 27837778
DOI: 10.1016/j.gtc.2016.07.003 -
Metabolism: Clinical and Experimental Aug 2016Nonalcoholic fatty liver disease (NAFLD) is the liver injury most often associated with disorders of insulin resistance, including obesity, diabetes and the metabolic... (Review)
Review
Nonalcoholic fatty liver disease (NAFLD) is the liver injury most often associated with disorders of insulin resistance, including obesity, diabetes and the metabolic syndrome. The term encompasses several patterns of liver injury, including a relatively benign condition of steatosis without hepatocellular injury, nonalcoholic steatohepatitis (NASH), and a pattern of zone 1 steatosis, inflammation and fibrosis mainly observed in prepubertal children. Staging and grading systems have been developed to characterize the histological changes in NAFLD, mainly as a tool for clinical research. The histological features of NAFLD across these different manifestations and the scoring systems used to evaluate disease severity are discussed.
Topics: Biopsy; Fatty Liver; Humans; Liver; Metabolic Syndrome; Non-alcoholic Fatty Liver Disease
PubMed: 26775559
DOI: 10.1016/j.metabol.2015.11.008 -
BMC Medicine Feb 2017Non-alcoholic fatty liver disease has emerged a major challenge because of it prevalence, difficulties in diagnosis, complex pathogenesis, and lack of approved... (Review)
Review
Non-alcoholic fatty liver disease has emerged a major challenge because of it prevalence, difficulties in diagnosis, complex pathogenesis, and lack of approved therapies. As the burden of hepatitis C abates over the next decade, non-alcoholic fatty liver disease will become the major form of chronic liver disease in adults and children and could become the leading indication for liver transplantation. This overview briefly summarizes the most recent data on the pathophysiology, diagnosis, and treatment of non-alcoholic fatty liver disease. Ongoing clinical trials are focused on an array of disease mechanisms and reviewed here are how these treatments fit into the current paradigm of substrate overload lipotoxic liver injury. Many of the approaches are directed at downstream events such as inflammation, injury and fibrogenesis. Addressing more proximal processes such as dysfunctional satiety mechanisms and inappropriately parsimonious energy dissipation are potential therapeutic opportunities that if successfully understood and exploited would not only address fatty liver disease but also the other components of the metabolic syndrome such as obesity, diabetes and dyslipidemia.
Topics: Adult; Child; Humans; Non-alcoholic Fatty Liver Disease
PubMed: 28241825
DOI: 10.1186/s12916-017-0806-8