Concise review of lipidomics in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) encompasses simple liver steatosis, nonalcoholic steatohepatitis (NASH), and liver fibrosis that can progress to cirrhosis. NAFLD has become the principal cause of chronic liver disease in many parts of the world. Lipidomic studies, by allowing to determine concentrations of lipid classes and fatty acid composition of different lipid species, have been of great interest to help understand NAFLD pathophysiology and potentially identify novel biomarkers for diagnosis and prognosis. Indeed, lipidomic data give information on qualitative lipid abnormalities associated with NAFLD. The aim of our article was to create a comprehensive and more synthetic review of main results from lipidomic studies in NAFLD. Literature was searched for all human lipidomic studies evaluating plasma samples of individuals with NAFLD. Results were regrouped by the degree of liver damage, either simple steatosis, NASH or liver fibrosis, and presented by lipid categories. Overall, we summarized the main lipidomic abnormalities associated with NAFLD as follows: modification of free fatty acid distribution, increase in ceramides, reduced phosphatidylcholine / phosphatidylethanolamine ratio, and increase in eicosanoids. These lipid abnormalities are likely to promote NASH and liver fibrosis by inducing mitochondrial dysfunction, apoptosis, inflammation, oxidation, and endoplasmic reticulum stress. Although these lipidomic abnormalities are consistently reported in many studies, further research is needed to clarify whether they may be predictive for liver steatosis, NASH or liver fibrosis.     

Non-alcoholic fatty liver disease and insulin resistance: From bench to bedside

Non-alcoholic fatty liver disease (NAFLD) is now the most frequent chronic liver disease in the developed countries. There is also growing evidence from basic and clinical research that NAFLD has a strong relationship to insulin resistance, which is a key factor in the development of type 2 diabetes. The aim of this review is to summarize the recent important findings linking NAFLD and insulin resistance. Lipid accumulation, particularly of diacylglycerol, appears to be of major importance in this process. Mitochondrial dysfunction, through decreased mitochondrial biogenesis, increases oxidative stress, and ageing also plays an important role. Finally, endoplasmic reticulum stress and inflammation also probably contribute to the development of insulin resistance via mechanisms that are still not well understood. Clinical aspects of NAFLD, such as its diagnosis and management, are also investigated in this review.     

The lysosomal-mitochondrial axis in free fatty acid-induced hepatic lipotoxicity

Impaired mitochondrial function is largely thought to be a core abnormality responsible for disease progression in nonalcoholic fatty liver disease (NAFLD). However, the molecular mechanisms resulting in mitochondrial dysfunction in NAFLD remain poorly understood. This study examined the effects of excessive accumulation of free fatty acids (FFAs) in liver cells on mitochondrial function and the role of the lysosomal-mitochondrial axis on lipotoxicity. Primary mouse hepatocytes, HepG2 and McNtcp.24 cells, were treated with varied concentrations of FFAs with different degrees of saturation for up to 24 hours. Mitochondrial function was monitored by real-time imaging, cytochrome c redistribution, and reactive oxygen species (ROS) production. The temporal relationship of lysosomal and mitochondrial permeabilization was established. Activity of the lysosomal protease cathepsin B was suppressed by genetic and pharmacological approaches. Cathepsin B-knockout mice and wild-type animals were place on a high-carbohydrate diet for 16 weeks, and mitochondrial function and liver damage were assessed. Exposure of liver cells to saturated FFAs resulted in mitochondrial depolarization, cytochrome c release, and increased ROS production. Lysosomal permeabilization and cathepsin B redistribution into the cytoplasm occurred several hours prior to mitochondrial dysfunction. Either pharmacological or genetic inhibition of cathepsin B preserved mitochondrial function. Finally, cathepsin B inactivation protected mitochondria, decreased oxidative stress, and attenuated hepatic injury in vivo. Conclusion: These data strongly suggest excessive accumulation of saturated FFAs in liver cells directly induce mitochondrial dysfunction and oxidative stress. Our data further suggest this process is dependent on lysosomal disruption and activation of cathepsin B.     

Chemokine ligand 2 and paraoxonase-1 in non-alcoholic fatty liver disease:The search for alternative causative factors

The incidence and prevalence of non-alcoholic fatty liver disease(NAFLD)is constantly increasing.Despite this is apparently associated with the growing increase in obesity,insulin resistance and obesity-related metabolic disturbances their presence is not a necessary or sufficient condition to explain the accumulation of fatin the liver.Conversely,NAFLD is a predictor of other metabolic risks.NAFLD is currently the most frequent chronic liver disease but should not be considered benign or anecdotic because a considerable proportion of patients with NAFLD progress to cirrhosis and endstage liver disease.Consequently,the search for alternative molecular mechanisms with therapeutic implications in NAFLD and associated disorders deserves a careful consideration.Mitochondria are possible targets as these organelles generate energy from nutrient oxidation.Some findings,generated in patients with extreme obesity and in murine models,support the notion that NAFLD could be a mitochondrial disease.This is plausible because mitochondrial dysfunction affects the accumulation of lipids in hepatocytes and promotes lipid peroxidation,the production of reactive oxygen species,the release of cytokines causing inflammation and cell death.Here we discuss basic research and mechanistic studies targeting the role of chemokine ligand 2 in liver inflammation and that of the paraoxonases in the oxidative stress.Their combination and association with mitochondrial dysfunction may uncover mechanisms underlying the progression of NAFLD and may help to identify novel therapeutic targets.     

血管紧张素Ⅱ-1受体及基因与非酒精性脂肪肝纤维化相关研究

血管紧张素Ⅱ-1受体（AT1R）作为血管紧张素Ⅱ的一个重要受体,在收缩血管,调节血压、血容量,维持机体水、电解质平衡等方面研究较多。非酒精性脂肪肝（NAFLD）是一种遗传-环境-代谢应激相关性疾病,发病机制至今仍不明确,目前已成为很多国家慢性肝功能损害的常见原因,易导致肝纤维化。最近的研究表明血管紧张素Ⅱ-1受体及其基因与非酒精性脂肪肝、肝纤维化发病密切相关。本文就近年来关于血管紧张素Ⅱ-1受体及其基因与非酒精性脂肪肝及纤维化的关系研究进行概述。     

Pathogenesis and management issues for non-alcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) has, although it is a very common disorder, only relatively recently gained broader interest among physicians and scientists.Fatty liver has been documented in up to 10 to 15percent of normal individuals and 70 to 80 percent of obese individuals. Although the pathophysiology of NAFLD is still subject to intensive research, several players and mechanisms have been suggested based on the substantial evidence. Excessive hepatocyte triglyceride accumulation resulting from insulin resistance is the first step in the proposed 'two hit' model of the pathogenesis of NAFLD. Oxidative stress resulting from mitochondrial fatty acids oxidation, NF-κB-dependent inflammatory cytokine expression and adipocytokines are all considered to be the potential factors causing second hits which lead to hepatocyte injury, inflammation and fibrosis. Although it was initially believed that NAFLD is a completely benign disorder, histologic follow-up studies have showed that fibrosis progression occurs in about a third of patients. A small number of patients with NAFLD eventually ends up with end-stage liver disease and even hepatocellular carcinoma. Although liver biopsy is currently the only way to confirm the NAFLD diagnosis and distinguish between fatty liver alone and NASH, no guidelines or firm recommendations can still be made as for when and in whom it is necessary. Increased physical activity, gradual weight reduction and in selected cases bariatric surgery remain the mainstay of NAFLD therapy. Studies with pharmacologic agents are showing promising results, but available data are still insufficient to make specific recommendations; their use therefore remains highly individual.     

Role of cytokines and chemokines in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) includes a variety of histological conditions (ranging from liver steatosis and steatohepatitis, to fibrosis and hepatocarcinoma) that are characterized by an increased fat content within the liver. The accumulation/deposition of fat within the liver is essential for diagnosis of NAFLD and might be associated with alterations in the hepatic and systemic inflammatory state. Although it is still unclear if each histological entity represents a different disease or rather steps of the same disease, inflammatory processes in NAFLD might influence its pathophysiology and prognosis. In particular, non-alcoholic steatohepatitis (the most inflamed condition in NAFLDs, which more frequently evolves towards chronic and serious liver diseases) is characterized by a marked activation of inflammatory cells and the upregulation of several soluble inflammatory mediators. Among several mediators, cytokines and chemokines might play a pivotal active role in NAFLD and are considered as potential therapeutic targets. In this review, we will update evidence from both basic research and clinical studies on the potential role of cytokines and chemokines in the pathophysiology of NAFLD.     

Natural history of NASH and HCC

Widespread unhealthy dietary habits associated with a sedentary lifestyle have made NAFLD the most frequent chronic liver disease worldwide, with a global prevalence of ~25%. Although NAFLD is mainly considered to be a benign disease, it can progress to severe liver fibrosis and hepatocellular carcinoma (HCC), with the latter found in non‐cirrhotic livers in about 40% of cases. Factors favouring the progression of liver disease in NAFLD are only partially understood. Male sex, older age and Caucasian ethnicity have frequently been identified as factors accelerating the progression of fibrosis in NAFLD, although data are not consistent. Host genetic variants appear to be very important, especially in the gene coding for the patatin‐like phospholipase domain‐containing 3 (PNPLA3), and they may also play a role in the development of HCC, independent of activity and the extent of liver damage. However, the most important factors affecting disease progression are found in the metabolic syndrome, that is, obesity, type 2 diabetes and arterial hypertension. This mini‐review will discuss the contribution of these factors to NAFLD‐associated morbidity, emphasizing the importance of preventive measures such as physical activity and weight control in view of the current pandemic of the metabolic syndrome.     

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.     

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.     

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.     

Mitochondrial reactive oxygen species as a mystery voice in hepatitis C

There are several lines of evidence suggesting that oxidative stress is present in hepatitis C to a greater degree than in other inflammatory liver diseases and is closely related to disease progression. The main production site of reactive oxygen species (ROS) is assumed to be mitochondria, which concept is supported by evidence that hepatitis C virus (HCV) core protein is directly associated with them. The detoxification of ROS also is an important function of the cellular redox homeostasis system. These results draw our attention to how HCV‐induced mitochondrial ROS production is beyond redox regulation and affects the disease progression and development of hepatocellular carcinoma (HCC) in chronic hepatitis C. On the other hand, HCV‐related chronic liver diseases are characterized by metabolic alterations such as insulin resistance, hepatic steatosis and/or iron accumulation in the liver. These metabolic disorders also are relevant to the development of HCC in HCV‐related chronic liver diseases. Here, we review the mechanisms by which HCV increases mitochondrial ROS production and offer new insights as to how mitochondrial ROS are linked to metabolic disorders such as insulin resistance, hepatic steatosis and hepatic iron accumulation that are observed in HCV‐related chronic liver diseases.     

Nonalcoholic fatty liver disease - A multisystem disease?

Non-alcoholic fatty liver disease(NAFLD) is one of the most common comorbidities associated with overweight and metabolic syndrome(Met S). Importantly, NAFLD is one of its most dangerous complications because it can lead to severe liver pathologies, including fibrosis, cirrhosis and hepatic cellular carcinoma. Given the increasing worldwide prevalence of obesity, NAFLD has become the most common cause of chronic liver disease and therefore is a major global health problem. Currently, NAFLD is predominantly regarded as a hepatic manifestation of Met S. However, accumulating evidence indicates that the effects of NAFLD extend beyond the liver and are negatively associated with a range of chronic diseases, most notably cardiovascular disease(CVD), diabetes mellitus type 2(T2DM) and chronic kidney disease(CKD). It is becoming increasingly clear that these diseases are the result of the same underlying pathophysiological processes associated with Met S, such as insulin resistance, chronic systemic inflammation and dyslipidemia. As a result, they have been shown to be independent reciprocal risk factors. In addition, recent data have shown that NAFLD actively contributes to aggravation of the pathophysiology of CVD, T2 DM, and CKD, as well as several other pathologies. Thus, NAFLD is a direct cause of many chronic diseases associated with MetS, and better detection and treatment of fatty liver disease is therefore urgently needed. As non-invasive screening methods for liver disease become increasingly available, detection and treatment of NAFLD in patients with MetS should therefore be considered by both(sub-) specialists and primary care physicians.     

肝血窦内皮细胞在非酒精性脂肪性肝病发展中的作用

非酒精性脂肪性肝病(NAFLD)是以肝脏脂肪变、炎症和纤维化为主要表现的临床代谢综合征,日渐成为严重影响公众健康的常见慢性肝病。肝血窦内皮细胞(LSEC)是肝脏组织特化的血管内皮细胞,作为一道重要的血管屏障,其对肝脏细胞吸收和代谢源自肠道血液中的营养与物质成分发挥重要调节作用。介绍了NAFLD发生发展进程中LSEC毛细血管化、血管功能障碍及其参与调控肝脏炎症、血管生成、肝纤维化的研究进展。     

Diagnostic and therapeutic implications of the association between ferritin level and severity of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD), defined by excessive liver fat deposition related to the metabolic syndrome, is a leading cause of progressive liver disease, for which accurate non-invasive staging systems and effective treatments are still lacking. Evidence has shown that increased ferritin levels are associated with the metabolic insulin resistance syndrome, and higher hepatic iron and fat content. Hyperferritinemia and iron stores have been associated with the severity of liver damage in NAFLD, and iron depletion reduced insulin resistance and liver enzymes. Recently, Kowdley et al demonstrated in a multicenter study in 628 adult patients with NAFLD from the NAFLD-clinical research network database with central re-evaluation of liver histology and iron staining that the increased serum ferritin level is an independent predictor of liver damage in patients with NAFLD, and is useful to identify NAFLD patients at risk of non-alcoholic steatohepatitis and advanced fibrosis. These data indicate that incorporation of serum ferritin level may improve the performance of noninvasive scoring of liver damage in patients with NAFLD, and that iron depletion still represents an attractive therapeutic target to prevent the progression of liver damage in these patients.     

Nonalcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD), the most common liver disorder in the Western world, is a clinico-histopathological entity in which excessive triglyceride accumulation in the liver occurs. Non-alcoholic steatohepatitis (NASH) represents the necroinflammatory form, which can lead to advanced liver fibrosis, cirrhosis, and hepatocellular carcinoma. The pathogenesis of NAFLD/NASH is complex but increased visceral adiposity plus insulin resistance with increased free fatty acids release play an initial key role for the onset and perpetuation of liver steatosis. Further events in the liver include oxidative stress and lipid peroxidation, decreased antioxidant defences, early mitochondrial dysfunction, iron accumulation, unbalance of adipose-derived adipokines with a chronic proinflammatory status, and gut-derived microbial adducts. New gene polymorphisms increasing the risk of fatty liver, namely APOC3 and PNPLA3, have been lately identified allowing further insights into the pathogenesis of this condition. In our review pathophysiological, genetic, and essential diagnostic and therapeutic aspects of NAFLD are examined with future trends in this field highlighted.     

Melatonin,cardiolipin and mitochondrial bioenergetics in health and disease

Abstract: Melatonin is a natural occurring compound with well‐known antioxidant properties. Melatonin is ubiquitously distributed and because of its small size and amphiphilic nature, it is able to reach easily all cellular and subcellular compartments. The highest intracellular melatonin concentrations are found in mitochondria, raising the possibility of functional significance for this targeting with involvement in situ in mitochondrial activities. Mitochondria, the powerhouse of the cell, are considered to be the most important cellular organelles to contribute to degenerative processes mainly through respiratory chain dysfunction and formation of reactive oxygen species, leading to damage to mitochondrial proteins, lipids and DNA. Therefore, protecting mitochondria from oxidative damage could be an effective therapeutic strategy against cellular degenerative processes. Many of the beneficial effects of melatonin administration may depend on its effect on mitochondrial physiology. Cardiolipin, a phospholipid located at the level of inner mitochondrial membrane is known to be intimately involved in several mitochondrial bioenergetic processes as well as in mitochondrial‐dependent steps of apoptosis. Alterations to cardiolipin structure, content and acyl chain composition have been associated with mitochondrial dysfunction in multiple tissues in several physiopathological situations and aging. Recently, melatonin was reported to protect the mitochondria from oxidative damage by preventing cardiolipin oxidation and this may explain, at least in part, the beneficial effect of this molecule in mitochondrial physiopathology. In this review, we discuss the role of melatonin in preventing mitochondrial dysfunction and disease.     

Angiotensin II-induced non-alcoholic fatty liver disease is mediated by oxidative stress in transgenic TG(mRen2)27(Ren2) rats

BACKGROUND/AIMS: Non-alcoholic fatty liver disease (NAFLD) is a common health problem and includes a spectrum of hepatic steatosis, steatohepatitis and fibrosis. The renin-angiotensin system (RAS) plays a vital role in blood pressure regulation and appears to promote hepatic fibrogenesis. We hypothesized that increased RAS activity causes NAFLD due to increased hepatic oxidative stress. METHODS: We employed the transgenic TG(mRen2)27(Ren2) hypertensive rat, harboring the mouse renin gene with elevated tissue Angiotensin II (Ang II). RESULTS: Compared with normotensive Sprague-Dawley (SD) control rats, Ren2 developed significant hepatic steatosis by 9 weeks of age that progressed to marked steatohepatitis and fibrosis by 12 weeks. These changes were associated with increased levels of hepatic reactive oxygen species (ROS) and lipid peroxidation. Accordingly, 9-week-old Ren2 rats were treated for 3 weeks with valsartan, an angiotensin type 1 receptor blocker, or tempol, a superoxide dismutase/catalase mimetic. Hepatic indices for oxidative stress, steatosis, inflammation and fibrosis were markedly attenuated by both valsartan and tempol treatment. CONCLUSIONS: This study suggests that Ang II causes development and progression of NAFLD in the transgenic Ren2 rat model by increasing hepatic ROS. Our findings also support a potential role of RAS in prevention and treatment of NAFLD.     

Liver fibrosis markers of nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) is one of the major causes of chronic liver injury. NAFLD includes a wide range of clinical conditions from simple steatosis to nonalcoholic steatohepatitis (NASH), advanced fibrosis, and liver cirrhosis. The histological findings of NASH indicate hepatic steatosis and inflammation with characteristic hepatocyte injury (e.g., ballooning degeneration), as is observed in the patients with alcoholic liver disease. NASH is considered to be a potentially health-threatening disease that can progress to cirrhosis. A liver biopsy remains the most reliable diagnostic method to appropriately diagnose NASH, evaluate the severity of liver fibrosis, and determine the prognosis and optimal treatment. However, this invasive technique is associated with several limitations in routine use, and a number of biomarkers have been developed in order to predict the degree of liver fibrosis. In the present article, we review the current status of noninvasive biomarkers available to estimate liver fibrosis in the patients with NASH. We also discuss our recent findings on the use of the glycated albumin-to-glycated hemoglobin ratio, which is a new index that correlates to various chronic liver diseases, including NASH.