Hepatic lipid metabolism and non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is an increasingly recognized pathology with a high prevalence and a possible evolution to its inflammatory counterpart (non-alcoholic steatohepatitis, or NASH). The pathophysiology of NAFLD and NASH has many links with the metabolic syndrome, sharing a causative factor in insulin resistance. According to a two-hit hypothesis, increased intrahepatic triglyceride accumulation (due to increased synthesis, decreased export, or both) is followed by a second step (or “hit”), which may lead to NASH. The latter likely involves oxidative stress, cytochrome P450 activation, lipid peroxidation, increased inflammatory cytokine production, activation of hepatic stellate cells and apoptosis. However, both “hits” may be caused by the same factors. The aim of this article is to overview the biochemical steps of fat regulation in the liver and the alterations occurring in the pathogenesis of NAFLD and NASH.     

Clinicopathological features of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease worldwide and its incidence is increasing concomitantly with the increase in the prevalence of metabolic syndrome. Fatty liver encompasses a broad pathological spectrum of disease, from relatively benign accumulation of fat (simple steatosis) to progressive non-alcoholic steatohepatitis (NASH), which is associated with necroinflammation and fibrosis. Approximately 20-30% of the Japanese population is estimated to have NAFLD, 10% of which is suggested to have NASH. The most worrisome feature of NASH is the potential progression to cirrhosis, hepatocellular carcinoma (HCC), and finally, mortality. Several factors, such as insulin resistance, adipokines, endotoxins and oxidative stress, are involved in the pathogenesis of NASH. However, the precise etiological mechanism of NAFLD/NASH has yet to be elucidated. This article reviews the clinical background, pathogenesis, new diagnostic approaches and future directions regarding NAFLD/NASH.     

Experimental models of non-alcoholic fatty liver disease in rats

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world, and it persists at a high prevalence. NAFLD is characterised by the accumulation of triglycerides in the liver and includes a spectrum of histopathological findings, ranging from simple fatty liver through non-alcoholic steatohepatitis (NASH) to fibrosis and ultimately cirrhosis, which may progress to hepatocellular carcinoma. The pathogenesis of NAFLD is closely related to the metabolic syndrome and insulin resistance. Understanding the pathophysiology and treatment of NAFLD in humans has currently been limited by the lack of satisfactory animal models. The ideal animal model for NAFLD should reflect all aspects of the intricate etiopathogenesis of human NAFLD and the typical histological findings of its different stages. Within the past several years, great emphasis has been placed on the development of an appropriate model for human NASH. This paper reviews the widely used experimental models of NAFLD in rats. We discuss nutritional, genetic and combined models of NAFLD and their pros and cons. The choice of a suitable animal model for this disease while respecting its limitations may help to improve the understanding of its complex pathogenesis and to discover appropriate therapeutic strategies. Considering the legislative, ethical, economical and health factors of NAFLD, animal models are essential tools for the research of this disease.     

Role of hepatic iron in non-alcoholic steatohepatitis

Non-alcoholic fatty liver disease (NAFLD) includes a spectrum of clinical entities ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) with possible evolution to cirrhosis and hepatocellular carcinoma. Iron is considered a putative element that interacts with oxygen radicals in inducing liver damage and fibrosis. The role of hepatic iron in the progression of NASH remains controversial, but in some patients, iron may have a role in the pathogenesis of NASH. Though genetic factors, insulin resistance, dysregulation of iron-regulatory molecules, erythrophagocytosis by Kupffer cells may be responsible for hepatic iron accumulation in NASH, exact mechanisms involved in iron overload remain to be clarified. Iron reduction therapy such as phlebotomy or dietary iron restriction may be promising in patients with NASH/NAFLD to reduce insulin resistance as well as serum transaminase activities.     

Impact of current treatments on liver disease,glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials

Aims/hypothesis  

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum ranging from simple steatosis to non-alcoholic steatohepatitis (NASH): NAFLD causes an increased risk of cardiovascular disease, diabetes and liver-related complications (the latter confined to NASH). The effect of proposed treatments on liver disease, glucose metabolism and cardiovascular risk in NAFLD is unknown. We reviewed the evidence for the management of liver disease and cardio-metabolic risk in NAFLD.     

Non-alcoholic Fatty Liver Disease and Cardiovascular Disease Risk

Non-alcoholic fatty liver disease (NAFLD) is an increasingly recognized cause of liver disease in the United States and worldwide. Increasing recognition of the importance of NAFLD and its strong relationship with the metabolic syndrome has stimulated an interest in the possible role of NAFLD in the development and progression of cardiovascular disease (CVD). Recent prospective studies demonstrated that NAFLD, especially in its necroinflammatory form (NASH), is linked to an increased risk of CVD, independently of obesity and other shared cardiometabolic risk factors. This suggests that NAFLD/NASH is not merely a marker of CVD, but may also be actively involved in its pathogenesis, possibly through the systemic release of proinflammatory/proatherogenic factors from the inflamed/steatotic liver as well as the contribution of NAFLD per se to whole-body insulin resistance and atherogenic dyslipidemia. Health care providers managing NAFLD patients should recognize this increased CVD risk and undertake early, aggressive risk factor modification.     

Klinische Bedeutung – Sinn und Unsinn – der Leberbiopsie bei NAFLD

Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum ranging from bland non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular cancer. Whereas “pure” NAFL rarely results in progressive liver disease, NASH can progress to liver cirrhosis in up to 25% of NASH patients. NAFL and NASH are both associated with an increased cardiovascular mortality, which represents the most important prognosis-limiting factor in both conditions. Diagnosis of NAFLD is based on clinical, biochemical, and sonographic findings. Liver biopsy is required for histologic distinction between NAFL and NASH. Because the therapeutic options for NASH are currently limited, liver biopsy has a rather limited value in the daily clinical management of NAFLD. Non-invasive laboratory and imaging methods (such as ultrasound elastography) may become increasingly important in the future.     

Host factors are dominant in the development of post-liver transplant non-alcoholic steatohepatitis

Non-alcoholic fatty liver disease (NAFLD) is a recognized problem in patients after orthotopic liver transplantation and may lead to recurrent graft injury. As the increased demand for liver allografts fail to match the available supply of donor organs, split liver transplantation (SLT) has emerged as an important technique to increase the supply of liver grafts. SLT allows two transplants to occur from one donor organ, and provides a unique model for observing the pathogenesis of NAFLD with respect to the role of recipient environmental and genetic factors. Here we report on two recipients of a SLT from the same deceased donor where only one developed non-alcoholic steatohepatitis (NASH), suggesting that host factors are critical for the development of NASH.     

Evaluation of ballooned hepatocytes as a risk factor for future progression of fibrosis in patients with non-alcoholic fatty liver disease

Journal of Gastroenterology - The prevalence of non-alcoholic fatty liver disease (NAFLD) has increased. Non-alcoholic steatohepatitis (NASH) shows progression of liver fibrosis in NAFLD. It...     

ASH and NASH

Non-alcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH) have a similar pathogenesis and histopathology but a different etiology and epidemiology. NASH and ASH are advanced stages of non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD). NAFLD is characterized by excessive fat accumulation in the liver (steatosis), without any other evident causes of chronic liver diseases (viral, autoimmune, genetic, etc.), and with an alcohol consumption ≤20-30 g/day. On the contrary, AFLD is defined as the presence of steatosis and alcohol consumption >20-30 g/day. The most common phenotypic manifestations of primary NAFLD/NASH are overweight/obesity, visceral adiposity, type 2 diabetes, hypertriglyceridemia and hypertension. The prevalence of NAFLD in the general population in Western countries is estimated to be 25-30%. The prevalence and incidence of NASH and ASH are not known because of the impossibility of performing liver biopsy in the general population. Up to 90% of alcoholics have fatty liver, and 5-15% of these subjects will develop cirrhosis over 20 years. The risk of cirrhosis increases to 30-40% in those who continue to drink alcohol. About 10-35% of alcoholics exhibit changes on liver biopsy consistent with alcoholic hepatitis. Natural histories of NASH and ASH are not completely defined, even if patients with NASH have a reduced life expectancy due to liver-related death and cardiovascular diseases. The best treatment of AFLD/ASH is to stop drinking, and the most effective first-line therapeutic option for NAFLD/NASH is non-pharmacologic lifestyle interventions through a multidisciplinary approach including weight loss, dietary changes, physical exercise, and cognitive-behavior therapy.     

Mechanisms of ductular reaction in non-alcoholic steatohepatitis

Non-alcoholic fatty liver disease (NAFLD) is a disease spectrum caused in part by insulin resistance and genetic predisposition. This disease is primarily characterized by excessive lipid accumulation in hepatocytes in the absence of alcohol abuse and other causes of liver damage. Histologically, NAFLD is divided into several periods: simple steatosis, non-alcoholic steatohepatitis (NASH), hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. With the increasing prevalence of obesity and hyperlipidemia, NAFLD has become the main cause of chronic liver disease worldwide. As a result, the pathogenesis of this disease is drawing increasing attention. Ductular reaction (DR) is a reactive bile duct hyperplasia caused by liver injury that involves hepatocytes, cholangiocytes, and hepatic progenitor cells. Recently, DR is shown to play a pivotal role in simple steatosis progression to NASH or liver fibrosis, providing new research and treatment options. This study reviews several DR signaling pathways, including Notch, Hippo/YAP-TAZ, Wnt/β-catenin, Hedgehog, HGF/c-Met, and TWEAK/Fn14, and their role in the occurrence and development of NASH.     

肠源性内毒素血症：非酒精性脂肪性肝炎的重要危险因素

非酒精性脂肪性肝病（NAFLD）是指除外酒精和其他明确损肝因素所致的、以肝细胞脂肪变性和脂质沉积为主要特征的临床病理综合征.非酒精性脂肪性肝炎（NASH）是NAFLD病程进展中的主要阶段.近年多项研究发现肠源性内毒素血症与NASH关系密切,本文就肠源性内毒素血症所致的肥胖和肝脏损伤对NASH发生的影响作一综述.     

Dietary lipids and NAFLD: suggestions for improved nutrition

Non-alcoholic fatty liver disease (NAFLD) ranges from steatosis and hepatic insulin resistance to non-alcoholic steatohepatitis (NASH), advanced fibrosis and cirrhosis. NAFLD is now considered as the hepatic manifestation of the metabolic syndrome, and both are triggered by mechanisms including inflammation, lipid overload and oxidative stress in adipose tissue and liver. Despite accumulation of numerous data on NAFLD physiopathology, therapeutic modulation of the pathways involved appear insufficiently efficient or associated with serious adverse effects. The increased prevalence of NAFLD and metabolic syndrome during the last decades was associated with deep modifications of dietary habits, especially increased fat intakes. Recent literature provides clues of increased saturated (SFA) and n-6 polyunsaturated fatty acids (PUFA) as well as reduced n-3 PUFA in the diet of NAFLD and NASH patients. Indeed, strong data support the detrimental role of high SFA and n-6/n-3 ratio as well as low monounsaturated fatty acids (MUFA) and n-3 PUFA on metabolic parameters, which are ameliorated by administration of n-3 PUFA and MUFA. Despite governments and health associations having revised their recommendations for n-3 PUFA intakes upward during the last decade, those are still inferior to levels proved of therapeutic efficiency and are still not reached in the general population. This short review discusses these issues and provides consequent pragmatic suggestions for enhanced dietary measures for prevention of NAFLD and metabolic syndrome in the general population.     

Clinical approaches to non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD)ranges from simple steatosis to nonalcoholic steatohepatitis(NASH),leading to fibrosis and potentially cirrhosis,and it is one of the most common causes of liver disease worldwide.NAFLD is associated with other medical conditions such as metabolic syndrome,obesity,cardiovascular disease and diabetes.NASH can only be diagnosed through liver biopsy,but noninvasive techniques have been developed to identify patients who are most likely to have NASH or fibrosis,reducing the need for liver biopsy and risk to patients.Disease progression varies between individuals and is linked to a number of risk factors.Mechanisms involved in the pathogenesis are associated with diet and lifestyle,influx of free fatty acids to the liver from adipose tissue due to insulin resistance,hepatic oxidative stress,cytokines production,reduced very low-density lipoprotein secretion and intestinal microbiome.Weight loss through improved diet and increased physical activity has been the cornerstone therapy of NAFLD.Recent therapies such as pioglitazone and vitamin E have been shown to be beneficial.Omega 3 polyunsaturated fatty acids and statins may offer additional benefits.Bariatric surgery should be considered in morbidly obese patients.More research is needed to assess the impact of these treatments on a long-term basis.The objective of this article is to briefly review the diagnosis,management and treatment of this disease in order to aid clinicians in managing these patients.     

Liver fat as risk factor of hepatic and cardiometabolic diseases

Non-alcoholic fatty liver disease (NAFLD) is a disorder characterized by excessive accumulation of fat in the liver that can progress to liver inflammation (non-alcoholic steatohepatitis [NASH]), liver fibrosis, and cirrhosis. Although most efforts for drug development are focusing on the treatment of the latest stages of NAFLD, where significant fibrosis and NASH are present, findings from studies suggest that the amount of liver fat may be an important independent risk factor and/or predictor of development and progression of NAFLD and metabolic diseases. In this review, we first describe the current tools available for quantification of liver fat in humans and then present the clinical and pathophysiological evidence that link liver fat with NAFLD progression as well as with cardiometabolic diseases. Finally, we discuss current pharmacological and non-pharmacological approaches to reduce liver fat and present open questions that have to be addressed in future studies.     

Lipidomics in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disorder in Western countries, comprises steatosis to nonalcoholic steatohepatitis (NASH), with the latter having the potential to progress to cirrhosis. The transition from isolated steatosis to NASH is still poorly understood, but lipidomics approach revealed that the hepatic lipidome is extensively altered in the setting of steatosis and steatohepatitis and these alterations correlate with disease progression. Recent data suggest that both quantity and quality of the accumulated lipids are involved in pathogenesis of NAFLD. Changes in glycerophospholipid, sphingolipid, and fatty acid composition have been described in both liver biopsies and plasma of patients with NAFLD, implicating that specific lipid species are involved in oxidative stress, inflammation, and cell death. In this article, we summarize the findings of main human lipidomics studies in NAFLD and delineate the currently available information on the pathogenetic role of each lipid class in lipotoxicity and disease progression.     

Cardiovascular risk across the histological spectrum and the clinical manifestations of non-alcoholic fatty liver disease:an update

Non-alcoholic fatty liver disease(NAFLD) is considered to be an independent cardiovascular disease(CVD)risk factor. However, simple steatosis has a benign clinical course without excess mortality. In contrast, the advanced form of NAFLD, non-alcoholic steatohepatitis(NASH) with liver fibrosis increases mortality by approximately 70%, due to an increase in CVD mortality by approximately 300%. Chronic kidney disease(CKD) may be caused by NAFLD/NASH and it substantially increases CVD risk, especially in the presence of type 2 diabetes mellitus. Moreover, CKD may trigger NAFLD/NASH deterioration in a vicious cycle. NAFLD/NASH is also related to increased arterial stiffness(AS), an independent CVD risk factor that further raises CVD risk. Diagnosis of advanced liver fibrosis(mainly by simple non-invasive tests), CKD,and increased AS should be made early in the course of NAFLD and treated appropriately. Lifestyle measures and statin treatment may help resolve NAFLD/NASH and beneficially affect the CVD risk factors mentioned above.     

改善胰岛素抵抗治疗NAFLD/NASH的循证证据

非酒精性脂肪性肝病/非酒精性脂肪性肝炎(NAFLD/NASH)是指除外酒精和其他明确的肝损伤因素所致的以肝细胞脂肪沉积为特征的临床病理综合征。胰岛素抵抗(IR)与NAFLD/NASH的发病密切相关,因此改善IR或许可以减轻肝损伤。多项随机对照临床试验显示胰岛素增敏剂和逐渐减轻体质量(饮食疗法或体育锻炼等)对NAFLD的治疗有一定作用,但长期疗效尚不明确。本文对近年关于改善IR治疗NAFLD/NASH的临床试验作一综述。     

The latest idea in NAFLD/NASH pathogenesis

Nonalcoholic fatty liver disease (NAFLD) is a metabolic disorder characterized by fatty accumulation in the liver without alcohol consumption. NAFLD ranges from simple steatosis to nonalcoholic steatohepatitis (NASH), which may progress to end-stage liver disease. The prevalence of NAFLD is rising because of an increasing prevalence of obesity and metabolic syndrome. The progression of these diseases is considered to be related to metabolic syndrome, which is characterized by obesity, glucose impairment, dyslipidemia, hypertension, and adipocytokine impairment. In addition, the pathogenesis of NAFLD/NASH is considered to be multifactorial and complex and is influenced by lifestyle habits, nutritional factors, and genetics. In particular, the PNPLA3 gene has been recently recognized as the most important functional gene polymorphism in the progression of NASH. Disruption in hepatic lipid metabolism is closely related to the development of fatty liver. Accumulation of excess triglycerides (TGs) induces hepatic steatosis. However, TG accumulation itself is not harmful to hepatocytes and may instead act as a protective mechanism against free fatty acid (FFA)-induced lipotoxicity. Excess FFAs also contribute to hepatotoxicity in NAFLD/NASH because oxidation of FFAs in hepatic microsomes generates excessive oxidative stress. Oxidative stress is considered one of the most important pathogenic factors in the development of NASH. Mitochondrial abnormalities, which are frequently observed in NASH-affected livers, are associated with impaired electron transport and result in further oxidative stress formation. The aims of this review are to assess the mechanisms of lipid metabolism and hepatic steatosis, the background of the disease, and the potential molecular mechanisms involved.     

Adiponectin, a key adipokine in obesity related liver diseases

Non-alcoholic fatty liver disease (NAFLD) comprising hepatic steatosis,non-alcoholic steatohepatitis (NASH),and progressive liver fibrosis is considered the most common liver disease in western countries.Fatty liver is more prevalent in overweight than normal-weight people and liver fat positively correlates with hepatic insulin resistance.Hepatic steatosis is regarded as a benign stage of NAFLD but may progress to NASH in a subgroup of patients.Besides liver biopsy no diagnostic tools to identify patients ...