Current Pharmaceutical Design - Volume 16, Issue 17, 2010

Nonalcoholic fatty liver disease (NAFLD) represents the hepatic manifestation of the metabolic syndrome and covers a large spectrum of liver diseases ranging from benign steatosis to steatohepatitis, cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD is currently believed to involve various hits including lipotoxicity, gut-derived signals, inflammatory attacks directed by pro-inflammatory cytokines, oxidative stress and others. All these factors finally lead to the development of necroinflammation and fibrosis in a substantial proportion of patients. There is increasing evidence that mediators released from the adipose tissue in obese subjects, such as adipocytokines and classical cytokines, are key players in NAFLD. The prototypic adipocytokines adiponectin and leptin are able to regulate many features of NAFLD such as accumulation of liver fat, insulin resistance, inflammatory processes and development of fibrosis. Therefore, this heterogenous and rapidly growing family of mediators elegantly explains many aspects of NAFLD as demonstrated by numerous experimental and clinical studies.

Recent studies revealed that adipose tissue is not only an energy storing organ, but is a kind of endocrine organ which secretes a variety of bioactive substances, so-called adipokines or adipocytokines. Visceral fat accumulation is associated with hypersecretion of adipocytokines such as tumor necrosis factor-alpha and plasminogen activator inhibitor-1 which may regulate inflammatory and atherogenic diseases. Adiponectin is a relatively new adipocytokine which we discovered in 1996 and has anti-diabetic, anti-atherogenic and anti-inflammatory properties. Adiponectin is present in plasma at a very high concentration, but in contrast to other adipocytokines, its production is reduced in subjects with visceral fat accumulation and the plasma levels are negatively correlated with visceral adiposity. Hypoadiponectinemia induced by visceral fat accumulation is closely associated with type 2 diabetes, lipid disorders, hypertension and also certain inflammatory diseases. In this review, the mechanisms of obesity-related diseases including nonalcoholic fatty liver disease will be discussed from the aspect of important roles of adipocytokines, especially adiponectin.

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome, whose pathogenesis begins with the accumulation of liver fat and is followed by the development of necro-inflammation and fibrosis. Recent evidence indicates that adipocytokines, polypeptides secreted by the adispose tissue, might play an important role in the pathogeneic process and progression of NAFLD. In this review, we explore the role of leptin, and in part of other adipocytokines, in the interference with hepatic injury associated with fatty infiltration, in the modulation of steatosis and fibrosis, in both experimental models of the disease and in the clinical practice. We also discuss the potential use of leptin as non-invasive marker for differentiating simple fatty liver from NAFLD, and the possible novel therapeutic strategies aimed at interfering with the leptin axis to dampen chronic liver inflammation and NAFLD.

Whereas prototypic adipocytokines such as adiponectin or leptin are mainly derived from adipocytes, others such as pre-B cell colony enhancing factor (PBEF)/nicotinamide phosphoribosyl transferase (NAMPT)/visfatin or resistin are produced by various cell types throughout the body. Although first discovery of this molecule as PBEF suggested primarily a cytokine function, its rediscovery as the key enzyme in nicotinamide adenine dinucleotide (NAD) generation has considerably widened its biological perspective. Finally, the same molecule was introduced as visfatin claiming an insulin-mimetic effect which has been questioned. Both extracellular (cytokinelike) and intracellular (enzymatic) functions are responsible for its relevance in immune, metabolic and stress responses. Its cytokine functions are mainly pro-inflammatory as it induces potently various other pro-inflammatory cytokines such as tumor necrosis factor alpha (TNFα) or interleukin-6 (IL-6). Its intracellular functions concentrate on the regulation of the activity of NAD-consuming enzymes such as various sirtuins thereby also affecting TNFα biosynthesis, cell life-span and longevity. Biochemical neutralization of PBEF/NAMPT/visfatin has been proven effective in various models of inflammation including sepsis/arthritis and in various models of cancer. Patients with non-alcoholic fatty liver disease (NAFLD) exhibit increased serum concentrations of PBEF/Nampt/visfatin and weight loss is associated both with a decrease in serum levels and reduced liver expression. Many of the biological functions of this “cytokine-enzyme” have been characterized in the last years, however, its definite role in various metabolic, inflammatory and malignant diseases has yet to be defined. (232 words)

Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent causes of hepatic dysfunction and is highly correlated with components of the metabolic syndrome such as obesity, insulin resistance and type 2 diabetes. Among others, nutritional factors, physical inactivity, genetic variants and visceral obesity have been identified as risk parameters for NAFLD. The complex pathophysiology of fatty liver degeneration, however, and especially the interaction between hepatocytes and adipose tissue has not been completely elucidated. Furthermore, it is not entirely understood whether insulin resistance generates fatty liver disease or vice versa. Nevertheless, adipocytokines are likely to be involved in the pathogenesis of NAFLD since they are secreted not only from adipose tissue but also from the liver. For several adipocytokines such as leptin, adiponectin, tumor necrosis factor-alpha, retinol binding protein 4 (RBP4) or fetuin-A a crucial role in the development and progression of fatty liver disease has been suggested. It has been accepted that obesity is an independent risk factor for NAFLD. Dysregulation of adipocytokines may represent an important mechanism linking increased fat mass in obesity with the development of fatty liver disease. Here, we discuss the association of RBP4 and other recently discovered adipocytokines and their relation with NAFLD.

Hepatic fibrosis is a dynamic process whereby the liver responds to conditions of persistent damage. This leads to deposition of fibrillar extracellular matrix, altered hepatocyte regeneration, deranged microvascular architecture and cirrhosis. Accumulating data demonstrate that obesity and insulin resistance are associated with a more severe and faster progression of the fibrogenic process in different chronic liver diseases, and attention has focused on possible links between the adipose tissue and liver repair. ADIPOCYTOKINEs are cytokines secreted primarily by adipose tissue, they are relevant for adipose tissue physiology and metabolism. Alterations in the adipocytokine pattern are involved in different obesity-related diseases, such as hypertension, atherosclerosis and type II diabetes mellitus (T2DM). Numerous recent studies have analyzed the role played by adipocytokines in the process of hepatic ‘wound healing’ and fibrogenesis. In particular, data have accumulated on the role of adiponectin and leptin. This review summarizes the more significant and recent findings concerning the role played by different adipocytokines in hepatic fibrogenesis, discussing the actions of adipocytokines on the biology of liver cells, and their effects in different animal models. The variations in the circulating levels and intrahepatic expression of different adipocytokines in patients with fibrogenic liver diseases are also discussed.

Nonalcoholic fatty liver disease (NAFLD) refers to a spectrum of liver damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), advanced fibrosis and cirrhosis. NAFLD is considered the hepatic component of the metabolic syndrome and insulin resistance represents its pathophysiological hallmark. Insulin resistance in NAFLD is characterized by reduced whole-body, hepatic, and adipose tissue insulin sensitivity. The mechanism(s) underlying the accumulation of fat in the liver may include excess dietary fat, increased delivery of free fatty acids to the liver, inadequate fatty acid oxidation, and increased de novo lipogenesis. Liver fat is highly correlated with all the components of the metabolic syndrome, independent of obesity, and NAFLD may increase the risk of type 2 diabetes and atherosclerosis. Overproduction of glucose, very low-density lipoproteins, C-reactive protein and coagulation factors by the fatty liver could contribute to the excess risk of cardiovascular disease. The reason(s) why some patients will develop NASH are poorly understood. Circulating free fatty acids may be cytotoxic by inducing lipid peroxidation and hepatocyte apoptosis. Insulin resistance is often associated with chronic low-grade inflammation, and numerous mediators released from immune cells and adipocytes may contribute liver damage and liver disease progression. Understanding the molecular mediators of liver injury would promote the development of mechanism-based therapeutic interventions. This article briefly summarizes the recent advances in our understanding of the relationship between NAFLD/NASH, insulin resistance and the metabolic syndrome.

The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is not entirely understood. Recently, the role of microRNA in this liver disease entity and its implication in disease pathogenesis and therapeutic potential has advanced rapidly over the year. While the regulation of miRNA function and its mechanism of actions on translational control of target mRNA expression remain unknown, advances in miRNA research allow identification and biochemical characterization of events that limit protein expression, which is crucial in various forms of human diseases and their subsequent development. It is hoped that further understanding of the role of microRNA in NAFLD will advance potential therapeutics and preventive measures to modify and alter this disease process.

Non alcoholic fatty liver disease (NAFLD) is increasingly diagnosed worldwide and considered to be the commonest liver disorder in Western countries. It comprises a disease spectrum ranging from simple steatosis (fatty liver), through non-alcoholic steatohepatitis (NASH) to fat with fibrosis and ultimately cirrhosis. Simple steatosis is largely benign and non-progressive, whereas NASH, characterized by hepatocyte injury, inflammation and fibrosis can lead to cirrhosis, liver failure and hepatocellular carcinoma (HCC). NAFLD is strongly associated with obesity, insulin resistance, hypertension and dyslipidaemia and is now regarded as the liver manifestation of the metabolic syndrome. Rapid spread of the obesity ‘pandemic’ in adults and children, coupled with the realisation that the outcomes of obesity-related liver disease are not entirely benign, has led to rapid growth in clinical and basic studies in NAFLD over the past decade. These studies are now beginning to inform management strategies for patients with NAFLD.

The liver is the most important target for toxicity caused by drugs. This vulnerability is a consequence of the functional features of the liver and their role in the metabolic elimination of most drugs. Therefore, evaluation of potential hepatotoxicity represents a critical step in the development of new drugs. The liver is very active in metabolising foreign compounds and, although biotransformation reactions generally parallel detoxification processes, the formation of reactive metabolites is relatively frequent. Thus, drug-induced hepatotoxicity can be due to the administered compound itself or to metabolites formed by hepatic metabolism. The most important systems to study hepatotoxicity and metabolic activity in vitro are liver slices, isolated liver cells in suspensions or in primary cultures including co-culture methods and special 3D techniques, various subcellular fractions and hepatic cell lines. These models can be used for cytotoxicity and genotoxicity screening, and also to identify the mechanisms involved in drug-induced hepatotoxicity. Assessment of current cytotoxicity and hepatic-specific biochemical effects are limited by the inability to measure a wide spectrum of potential mechanistic changes involved in the drug-induced toxic injury. A convenient selection of end-points allows a multiparametric evaluation of drug toxicity. In this regard, omic (cytomic, metabonomic, proteomic and toxicogemic) approaches help defining patterns of hepatotoxicity for early identification of potential adverse effects of the drug to the liver. The development of robust in vitro-based multiparametric screening assays covering a wider spectrum of key effects will heighten the predictive capacity for human hepatotoxicity, and accelerate the drug development process.