Cytokines in the pathogenesis of fatty liver and disease progression to steatohepatitis: implications for treatment

Nonalcoholic fatty liver disease (NAFLD) has emerged as a growing public health problem worldwide. NAFLD represents a wide spectrum of conditions ranging from fatty liver, that in general follows a benign nonprogressive clinical course, to nonalcoholic steatohepatitis (NASH), a serious form of NAFLD, that may progress to cirrhosis and end-stage liver disease. The mechanisms responsible for NAFLD development and disease progression remain incompletely understood, but are of great clinical interest as current therapies are limited. Future therapies will be predicted based upon the understanding of its pathogenesis. This review focuses on the growing evidence from both experimental and human studies suggesting a central role of cytokines in the pathogenesis of NAFLD. We review the role of cytokines as key regulators of insulin sensitivity and hepatic lipid overloading, liver injury and inflammation, and fibrosis and cirrhosis, with an emphasis on potential therapeutic implications.     

Nonalcoholic fatty liver disease as a multi-systemic disease

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. NAFLD includes a wide spectrum of liver conditions ranging from simple steatosis to nonalcoholic steatohepatitis and advanced hepatic fibrosis. NAFLD has been recognized as a hepatic manifestation of metabolic syndrome linked with insulin resistance. NAFLD should be considered not only a liver specific disease but also an early mediator of systemic diseases. Therefore, NAFLD is usually associated with cardiovascular disease, chronic kidney disease, type 2 diabetes, obesity, and dyslipidemia. NAFLD is highly prevalent in the general population and is associated with increased cardiovascular morbidity and mortality. The underlying mechanisms and pathogenesis of NAFLD with regard to other medical disorders are not yet fully understood. This review focuses on pathogenesis of NAFLD and its relation with other systemic diseases.     

Role of gut microbial metabolites in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a common, multifactorial liver disease that has emerged as a global challenge due to its increasing prevalence and lack of sustainable treatment options. Gut microbiota possess vital functions in fermenting dietary nutrients and synthesizing bioactive molecules. This function is of great importance in maintaining health because these microbial metabolites are essential in regulating energy metabolism, immune response, and other vital physiological processes. Altered gut flora can result in a change in gut microbial metabolites, affecting the onset and progression of multiple diseases. In this review we summarize the metabolites that may have beneficial or harmful effects on the development and progression of NAFLD. This will help us better understand the possible mechanisms underlying the pathogenesis of NAFLD and facilitate the identification of potential therapeutic approaches for NAFLD.     

Ghrelin-ghrelin O-acyltransferase system in the pathogenesis of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD) is currently considered as the most common liver disease in Western countries,and is rapidly becoming a serious threat to public health worldwide.However,the underlying mechanisms leading to the development of NAFLD are still not fully understood.The ghrelin-ghrelin O-acyltransferase(GOAT) system has recently been found to play a crucial role in both the development of steatosis and its progression to nonalcoholic steatohepatitis.Ghrelin,the natural ligand of the growth hormone secretagogue receptor,is a 28-amino acid peptide possessing a unique acylation on the serine in position 3 catalyzed by GOAT.The ghrelin-GOAT system is involved in insulin resistance,lipid metabolism dysfunction,and inflammation,all of which play important roles in the pathogenesis of NAFLD.A better understanding of ghrelin-GOAT system biology led to the identification of its potential roles in NAFLD.Molecular targets modulating ghrelin-GOAT levels and the biologic effects are being studied,which provide a new insight into the pathogenesis of NAFLD.This review probes into the possible relationship between the ghrelin-GOAT system and NAFLD,and considers the potential mechanisms by which the ghrelin-GOAT system brings about insulin resistance and other aspects concerning NAFLD.     

MicroRNAs as controlled systems and controllers in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is a multi-faceted condition including simple steatosis alone or associated with inflammation and ballooning (non-alcoholic steatohepatitis) and eventually fibrosis. The NAFLD incidence has increased over the last twenty years becoming the most frequent chronic liver disease in industrialized countries. Obesity, visceral adiposity, insulin resistance, and many other disorders that characterize metabolic syndrome are the major predisposing risk factors for NAFLD. Furthermore, different factors, including genetic background, epigenetic mechanisms and environmental factors, such as diet and physical exercise, contribute to NAFLD development and progression. Several lines of evidence demonstrate that specific microRNAs expression profiles are strongly associated with several pathological conditions including NAFLD. In NAFLD, microRNA deregulation in response to intrinsic genetic or epigenetic factors or environmental factors contributes to metabolic dysfunction. In this review we focused on microRNAs role both as controlled and controllers molecules in NAFLD development and/or their eventual value as non-invasive biomarkers of disease.     

Role of endoplasmic reticulum stress in the pathogenesis of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD)has emerged as a common public health problem in recent decades.However,the underlying mechanisms leading to the development of NAFLD are not fully understood.The endoplasmic reticulum(ER)stress response has recently been proposed to play a crucial role in both the development of steatosis and progression to nonalcoholic steatohepatitis.ER stress is activated to regulate protein synthesis and restore homeostatic equilibrium when the cell is stressed due to the accumulation of unfolded or misfolded proteins.However,delayed or insufficient responses to ER stress may turn physiological mechanisms into pathological consequences,including fat accumulation,insulin resistance,inflammation,and apoptosis,all of which play important roles in the pathogenesis of NAFLD.Therefore,understanding the role of ER stress in the pathogenesis of NAFLD has become a topic of intense investigation.This review highlights the recent findings linking ER stress signaling pathways to the pathogenesis of NAFLD.     

肠道屏障功能在非酒精性脂肪性肝病发病机制中的作用

非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)是一种常见的慢性肝脏疾病,且发病率有逐年上升的趋势.关于其发病的具体机制的研究从未停止.自马歇尔(Marshall)于1998年正式提出了"肠-肝轴"的概念,肠道屏障功能在NAFLD发病机制中的作用逐渐成为关注的重点.肠道屏障功能的4大方面机械屏障、化学屏障、生物屏障、免疫屏障相互密切联系,并且与NAFLD之间的关系也密不可分.本文对近年来关于肠道屏障功能与NAFLD的发生和发展的相关性研究结果进行综述,旨在探讨在NAFLD的发病机制中肠道屏障功能所起到的作用.     

MicroRNAs as biomarkers and regulators of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a complicated disease affected by the interaction of environmental and genetic factors; however, the precise pathogenesis of the disease has not been fully determined. There is a need to better understand the pathogenesis of NAFLD and to identify non‐invasive diagnostic modalities. Recent advances in systematic biology and epigenetics have improved our understanding of the genotype–phenotype relationships in NAFLD. MicroRNAs (miRNAs) are important regulators of a wide range of biological processes. MiRNAs are extremely stable and protect from RNAase‐mediated degradation in body fluids, making them attractive candidate biomarkers for the early detection of the disease and the monitoring of disease progression. In this review, we summarized the current knowledge on miRNAs as potential biomarkers of NAFLD at different stages and for the prognosis of advanced diseases. Furthermore, we discussed the implications of miRNAs that functioning in lipid metabolism and hepatic steatosis as well as in hepatic inflammation and fibrosis with regard to the pathogenesis of NAFLD.     

非酒精性脂肪性肝病血清标志物研究进展

目的 非酒精性脂肪性肝病(NAFLD)是目前全球最流行的慢性肝脏疾病,其主要发生机制包括胰岛素抵抗和氧化应激等.不同血清标志物与NAFLD发病机制密切相关,但尚无明确的定论.本文主要就NAFLD发生发展过程中不同血清标志物的作用作一综述.     

Probiotics in non-alcoholic fatty liver disease: which and when

Non-alcoholic fatty liver disease (NAFLD) is a common and serious disease. Literature reports the central role of the gut-liver axis in the pathogenesis of NAFLD, and recently suggests that the microbiota is a casual factor of the disease, involved in the interactions between intestinal lumen and liver. Probiotic are commensal bacteria, able to modulate the microbiota with benefits for the health of humans. Several data suggest a range of potentially beneficial medicinal uses for probiotics, in particular in NAFLD patients. However, the species with higher efficacy in this disease are not identified. The present review focuses on the role of gut-liver axis in the pathogenesis, and on the potential therapeutic role of probiotics in the managing of NAFLD.     

Iron and non-alcoholic fatty liver disease

The mechanisms that promote liver injury in non-alcoholic fatty liver disease(NAFLD) are yet to be thoroughly elucidated. As such, effective treatment strategies are lacking and novel therapeutic targets are required. Iron has been widely implicated in the pathogenesis of NAFLD and represents a potential target for treatment. Relationships between serum ferritin concentration and NAFLD are noted in a majority of studies, although serum ferritin is an imprecise measure of iron loading. Numerous mechanisms for a pathogenic role of hepatic iron in NAFLD have been demonstrated in animal and cell culture models. However, the human data linking hepatic iron to liver injury in NAFLD is less clear, with seemingly conflicting evidence, supporting either an effect of iron in hepatocytes or within reticulo-endothelial cells. Adipose tissue has emerged as a key site at which iron may have a pathogenic role in NAFLD. Evidence for this comes indirectly from studies that have evaluated the role of adipose tissue iron with respect to insulin resistance. Adding further complexity, multiple strands of evidence support an effect of NAFLD itself on iron metabolism. In this review, we summarise the human and basic science data that has evaluated the role of iron in NAFLD pathogenesis.     

Non-alcoholic fatty liver disease: An update with special focus on the role of gut microbiota

Non-alcoholic fatty liver disease (NAFLD) is a significant global health burden in children, adolescents and adults with substantial rise in prevalence over the last decades. Accumulating data from manifold studies support the idea of NAFLD as a hepatic manifestation of metabolic syndrome, being rather a systemic metabolic disease than a liver confined pathology. Emerging data support that the gut microbiome represents a significant environmental factor contributing to NAFLD development and progression. Apart from other regimens, probiotics may have a positive role in the management of NAFLD through a plethora of possible mechanisms. The current review focuses on the NAFLD multifactorial pathogenesis, including mainly the role of intestinal microbiome and all relevant issues are raised. Furthermore, the clinical manifestations and appropriate diagnostic approach of the disease are discussed, with all possible therapeutic measures that can be taken, also including the potential beneficial effect of probiotics.     

Pathogenesis of hypothyroidism-induced NAFLD: Evidence for a distinct disease entity?

Nonalcoholic fatty liver disease (NAFLD), the most common liver disease worldwide, may be associated with primary hypothyroidism. However, the pathogenesis underlying such an association is complex and not completely understood. Here, we specifically discuss the pathogenic mechanisms potentially involved in hypothyroidism-induced NAFLD. To this end, we summarize the general pathophysiology of thyroid hormones (TH). Next, we analyze the published data from rodent studies by discussing whether hypothyroid rats may develop NAFLD via hyperphagia; whether mitochondria become energetically more efficient; what the overall energy balance is and if diversion of fatty substrates occurs; and the latest advancements in molecular pathogenesis brought about by metabolomics, cell imaging, lipophagy, autophagy and genetically engineered mouse models. Moreover, we discuss the data published regarding humans on the pathogenic role of TH, metabolic syndrome and other risk factors in hypothyroidism-related NAFLD as well as the putative mechanisms underlying the development of NAFLD-related hepatocellular carcinoma in hypothyroidism. In conclusion, although many research questions still remain unanswered, the pathophysiology of hypothyroidism-induced NAFLD makes this a potentially curable and distinct disease entity. However, further studies are needed to better elucidate the underlying mechanisms, and to ascertain whether treatment with either TH or thyromimetic agents improves NAFLD.     

Antioxidant dietary approach in treatment of fatty liver: New insights and updates

Non-alcoholic fatty liver disease(NAFLD) is a common clinicopathological condition, encompassing a range of conditions caused by lipid deposition within liver cells. To date, no approved drugs are available for the treatment of NAFLD, despite the fact that it represents a serious and growing clinical problem in the Western world. Identification of the molecular mechanisms leading to NAFLD-related fat accumulation, mitochondrial dysfunction and oxidative balance impairment facilitates the development of specific interventions aimed at preventing the progression of hepatic steatosis. In this review, we focus our attention on the role of dysfunctions in mitochondrial bioenergetics in the pathogenesis of fatty liver. Major data from the literature about the mitochondrial targeting of some antioxidant molecules as a potential treatment for hepatic steatosis are described and critically analysed. There is ample evidence of the positive effects of several classes of antioxidants, such as polyphenols(i.e., resveratrol, quercetin, coumestrol, anthocyanins, epigallocatechin gallate and curcumin), carotenoids(i.e., lycopene, astaxanthin and fucoxanthin) and glucosinolates(i.e., glucoraphanin, sulforaphane, sinigrin and allyl-isothiocyanate), on the reversion of fatty liver. Although the mechanism of action is not yet fully elucidated, in some cases an indirect interaction with mitochondrial metabolism is expected. We believe that such knowledge will eventually translate into the development of novel therapeutic approaches for fatty liver.     

Tumor necrosis factor and its potential role in insulin resistance and nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of hepatic pathology that resembles alcohol-induced fatty liver disease(AFLD), but which develops in individuals who are not heavy drinkers. In people, NAFLD is associated strongly with obesity,insulin resistance, and dysmetabolic syndrome, but the exact mechanisms that promote liver disease in this clinical context remain poorly understood. The proinflammatory cytokine, funor necrosis factor alpha is known to be a key mediator of AFLD. This article discusses clinical and experimental evidence that tumor necrosis factor plays a role in the pathogenesis of insulin resistance syndromes, including nonalcoholic fatty syndromes, including nonalcoholic fatty liver disease.     

Non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease that affects a high proportion of the world's population. Insulin resistance and oxidative stress play a critical role in the pathogenesis of NAFLD. Clinical, biochemical and imaging studies are of value in the diagnostic evaluation of patients with NAFLD, but liver biopsy remains the most sensitive and specific means of providing important diagnostic and prognostic information. Simple steatosis has the best prognosis within the spectrum of NAFLD, but NAFLD has the potential to progress to steatohepatitis, fibrosis and even cirrhosis. No effective medical therapy is currently available for all patients with NAFLD. In patients with diabetes mellitus and hyperlipidemia, appropriate metabolic control is always recommended, but rarely effective in resolving the liver disease. Weight reduction, when achieved and sustained, may improve the liver disease, although the results with weight loss have been inconsistent. Pharmacological therapy aimed at the underlying liver disease holds promise. Several medications with different mechanisms of action and potential benefit are currently being evaluated in clinical trials. Liver transplantation is a life-extending therapeutic alternative for patients with end-stage NAFLD, but NAFLD may recur after liver transplantation.     

Genetic background in nonalcoholic fatty liver disease: A comprehensive review

In the Western world, nonalcoholic fatty liver disease(NAFLD) is considered as one of the most significant liver diseases of the twenty-first century. Its development is certainly driven by environmental factors, but it is also regulated by genetic background. The role of heritability has been widely demonstratedby several epidemiological, familial, and twin studies and case series, and likely reflects the wide interindividual and inter-ethnic genetic variability in systemic metabolism and wound healing response processes. Consistent with this idea, genome-wide association studies have clearly identified Patatin-like phosholipase domain-containing 3 gene variant I148 M as a major player in the development and progression of NAFLD. More recently, the transmembrane 6 superfamily member 2 E167 K variant emerged as a relevant contributor in both NAFLD pathogenesis and cardiovascular outcomes. Furthermore, numerous casecontrol studies have been performed to elucidate the potential role of candidate genes in the pathogenesis and progression of fatty liver, although findings are sometimes contradictory. Accordingly, we performed a comprehensive literature search and review on the role of genetics in NAFLD. We emphasize the strengths and weaknesses of the available literature and outline the putative role of each genetic variant in influencing susceptibility and/or progression of the disease.     

Nonalcoholic fatty liver disease and vascular disease:State-of-the-art

Nonalcoholic fatty liver disease(NAFLD), the most common of chronic liver disease in Western Country, is closely related to insulin resistance and oxidative stress and includes a wide spectrum of liver diseases ranging from steatosis alone, usually a benign and non-progressive condition, to nonalcoholic steatohepatitis(NASH), which may progress to liver fibrosis and cirrhosis. NAFLD is considered the hepatic manifestation of the metabolic syndrome with which shares several characteristics, however recent data suggest that NAFLD is linked to increased cardiovascular risk independently of the broad spectrum of risk factors of metabolic syndrome. Accumulating evidence suggests that the clinical burden of NAFLD is not restricted to liver-related morbidity and mortality, with the majority of deaths in NAFLD patients related to cardiovascular disease and cancer and not to the progression of liver disease. Retrospective and prospective studies provide evidence of a strong association between NAFLD and subclinical manifestation of atherosclerosis(increased intima-media thickness, endothelial dysfunction, arterial stiffness, impaired left ventricular function and coronary calcification). A general agreement emerging from these studies indicates that patients with NASH are at higher risk of cardiovascular diseases than those with simple steatosis, emphasizing the role of chronic inflammation in the pathogenesis of atherosclerosis of these patients. It is very likely that the different mechanisms involved in the pathogenesis of atherosclerosis in patients with NAFLD have a different relevance in the patients according to individual genetic background. In conclusion, in the presence of NAFLD patients should undergo a complete cardiovascular evaluation to prevent future atherosclerotic complications. Specific lifestyle modification and aggressive pharmaceutical modification will not only reduce the progression of liver disease, but also reduce morbidity for cardiovascular disease improving overall prognosis and survival.