Systematic review: association of polycystic ovary syndrome with metabolic syndrome and non-alcoholic fatty liver disease

Aliment Pharmacol Ther 2011; 33: 801–814

Summary

Background Polycystic ovary syndrome (PCOS) is a common disorder for women of child‐bearing age and is associated with metabolic syndrome (MS). Aim To assess the literature for associations between polycystic ovary syndrome and non‐alcholic fatty liver disease (NAFLD). Methods We performed a systematic review using PubMed‐search for peer‐reviewed articles related to polycystic ovary syndrome and NAFLD. Articles were summarised and grouped according to different sections defining interactions of polycystic ovary syndrome with metabolic syndrome and non‐alcholic fatty liver disease as well as risk factors, pathogenic pathways and treatment options. Results Obesity is a common factor involved in both polycystic ovary syndrome and non‐alcholic fatty liver disease. Obesity causes non‐alcholic fatty liver disease and aggravates hirsutism and menstrual disorders in polycystic ovary syndrome. Insulin resistance, a hallmark of metabolic syndrome is observed in 50–80% of women with polycystic ovary syndrome and patients with non‐alcholic fatty liver disease. Recent findings suggest that women with polycystic ovary syndrome may be at risk for developing non‐alcholic fatty liver disease and conversely, non‐alcholic fatty liver disease may be a risk for polycystic ovary syndrome. Based on the association of polycystic ovary syndrome and other metabolic abnormalities, such as insulin resistance, hyperandrogenism, obesity and non‐alcholic fatty liver disease, the candidate genes have been speculated for polycystic ovary syndrome. Closer scrutiny of these genes placed most of their proteins at the crossroads of three highly inter‐related conditions: metabolic syndrome, obesity and non‐alcholic fatty liver disease. In most studies, the prevalence of both polycystic ovary syndrome and non‐alcholic fatty liver disease rises proportionally to the degree of insulin resistance and increases in the mass of adipose tissue. Conclusions Non‐alcholic fatty liver disease is considered as the hepatic manifestation of metabolic syndrome. Similarly, it seems appropriate to consider polycystic ovary syndrome as the ovarian manifestation of metabolic syndrome. Both these conditions can co‐exist and may respond to similar therapeutic strategies.     

41例学龄儿童非酒精性脂肪性肝病代谢综合征分析

目的：研究学龄儿童非酒精性脂肪性肝病（NAFLD）患儿中代谢综合征（MS）的发病情况,探讨学龄儿童非酒精性脂肪性肝病的MS关系。方法：选取在本院就诊的NAFLD患儿41例作为NAFLD组,同期住院的的60例单纯性肥胖患儿作为对照组,检测体质量、身高、血压、腹围、血生化、空腹血糖及肝脏彩色多普勒超声检查,分析两组代谢综合征发生率及生化改变。结果：NAFLD组和对照组比较,除TG外NAFLD组ALT、AST、ALT/AST及TC均较对照组升高,而NAFLD组HDL-c低于对照组;NAFLD组MS发生率为41.46%,高于对照组的21.67%,两者比较差异有统计学意义（χ2=4.57,P=0.03）。结论：肥胖儿童若合并NAFLD,则其发生MS的风险明显增加。NAFLD的早期应当积极地改变生活方式、减轻体重、调节血脂、控制血糖,使肝脏损害早期逆转,防止或减缓其进一步发展。     

Elevation of liver enzymes within the normal limits and metabolic syndrome

1. Metabolic syndrome is frequently associated with elevated liver enzymes. However, the current 'normal' limits for liver enzymes often fail to identify patients with metabolic syndrome and the associated non-alcoholic fatty liver disease (NAFLD). 2. In the present study, 1503 participants, aged between 18 and 95 years, were recruited from the physical examination centre of Shanghai Zhongshan Hospital and Shanghai Changfeng Community Health Centre. The association between liver enzymes within the 'normal' range and metabolic syndrome was investigated and optimal cut-off values for liver enzymes in metabolic syndrome were determined. We further compared the diagnostic performance of the new cut-off values for liver enzymes in metabolic syndrome and NAFLD with the traditional 'normal' range for liver enzymes. 3. Serum liver enzymes within the traditional 'normal' limits, especially alanine aminotransferase (ALT) and γ-glutamyl transpeptidase (GGT), were correlated with most of components of the metabolic syndrome, as determined by Spearman's partial correlation analysis. Logistic regression analysis revealed that within the 'normal' range of liver enzymes, the frequency of metabolic syndrome was significantly increased in the higher quintile for ALT and GGT compared with the lowest quintile. Receiver operating characteristic curve analysis revealed that the optimal cut-off values for ALT, aspartate aminotransferase and GGT to identify metabolic syndrome were 26, 25 and 29 U/L, respectively, in men and 20, 23 and 21 U/L, respectively, in women. These values were much more effective in detecting patients with potential metabolic syndrome and NAFLD than the traditional cut-off values. 4. A slight elevation of liver enzymes within the 'normal' limits, especially ALT and GGT, indicates the presence of metabolic syndrome and NAFLD. Revision of the current normal limits for liver enzymes is advisable so that patients with potential metabolic disorders can be identified.     

Are statins ‘IDEAL’ for non-alcoholic fatty liver disease?

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and cause of elevated serum liver enzyme activities in the developed world1. Obesity, diabetes mellitus (DM), and dyslipidaemia, common components of the metabolic syndrome (MetS), are frequently associated with NAFLD; 75–100% of patients with MetS or DM have NAFLD2. NAFLD is characterized by hepatic triglyceride (TG) infiltration in the absence of alcohol abuse or chronic liver disease1. NAFLD includes a spectrum of conditions varying from steatosis to steatosis with inflammation [steatohepatitis (NASH)], necrosis, fibrosis or cirrhosis that rarely progresses to hepatocellular carcinoma3. NAFLD and NASH are the hepatic manifestations of MetS and are associated with increased cardiovascular disease (CVD) risk4. Most NAFLD/NASH patients die from CVD rather than from liver disease4,5. There is no universally accepted treatment for NAFLD1-5.     

肾素-血管紧张素系统阻断剂治疗代谢综合征的进展

代谢综合征以胰岛素抵抗为主要特征,是心血管疾病的危险因素。非酒精性脂肪性肝病（non—alcoholic fatty liver disease,NAFLD）是代谢综合征在肝脏的表现。肾素-血管紧张素系统（renin—angiotensin system,RAS）的激活参与了代谢综合征的发生、发展,阻断RAS的激活是代谢综合征的治疗途径之-。RAS阻断剂包括血管紧张素转换酶抑制剂（angiotensin converting enzyme inhibitor, ACEI）和血管紧张素Ⅱ受体拮抗剂（angiotensin receptor blockade, ARB）,可降低血压、改善胰岛β细胞功能和胰岛素抵抗,但RAS阻断剂对NAFLD的疗效尚存在争议。该文就RAS阻断剂治疗代谢综合征的进展进行了综述。     

Nonalcoholic fatty liver disease: pathogenesis and potential for nuclear receptors as therapeutic targets

Nonalcoholic fatty liver disease (NAFLD) is a consequence of insulin resistance encompassing a spectrum that extends from simple hepatic steatosis through to nonalcoholic steatohepatitis (NASH), a condition that may progress to cirrhosis with its associated complications. A subset of nuclear receptors act as intracellular sensors for cholesterol metabolites, free fatty acids, and a range of other lipophilic molecules with pivotal roles in energy homeostasis and inflammation. These receptors represent attractive drug targets for the management of NAFLD and NASH as well as related conditions such as type 2 diabetes and the broader metabolic syndrome. To date, human studies have concentrated on peroxisome proliferator-activated receptor (PPAR) agonists, particularly those directed at PPARgamma. However, these drugs have significant limitations, so alternate approaches to nuclear receptor targeting are being explored.     

Current treatment strategies for non-alcoholic fatty liver disease (NAFLD)

Nonalcoholic fatty liver disease (NAFLD) is recognized as the most common cause of chronic liver disease worldwide. NAFLD is a clinicopathologic syndrome ranging from simple steatosis, which is relatively benign, to the more severe form known as nonalcoholic steatohepatitis (NASH), which may progress to cirrhosis, liver failure, and hepatocellular carcinoma. NAFLD is associated with significant liver related morbidity and mortality, and its underlying pathophysiology is thought to result from a multiple hit process. The initial insult is the accumulation of hepatic fat secondary to insulin resistance. In the setting of hepatic steatosis, the second hit can be caused by reactive oxygen species, inflammatory cytokines, and adipokines. Several therapeutic modalities that target these mechanisms are under investigation, but no proven treatment has yet emerged. Insulin sensitizers such as thiazolidinediones and metformin show promise, and several studies have explored the role of lipid lowering agents, antioxidants, and cytoprotective agents. Novel agents such as anti-obesity drugs, selective cannabinoid-1 receptor blockers, and dual PPAR alpha and gamma agonists are also under investigation. Unfortunately, data on the long-term safety and efficacy of these agents and their impact on liver related histologic outcomes are currently lacking. NAFLD treatment currently focuses on reducing metabolic risk factors, with the mainstay of therapy focusing on life-style modifications such as gradual weight loss through diet and regular exercise.     

G protein-coupled receptor 35 attenuates nonalcoholic steatohepatitis by reprogramming cholesterol homeostasis in hepatocytes

Nonalcoholic fatty liver disease(NAFLD) is the most common chronic liver disease worldwide.Fat accumulation "sensitizes" the liver to insult and leads to nonalcoholic steatohepatitis(NASH).G protein-coupled receptor 35(GPR35) is involved in metabolic stresses,but its role in NAFLD is unknown.We report that hepatocyte GPR35 mitigates NASH by regulating hepatic cholesterol homeostasis.Specifically,we found that GPR35 overexpression in hepatocytes protected against high-fat/cholesterol/fructose(HFC...     

Methodologies for investigating natural medicines for the treatment of nonalcoholic fatty liver disease (NAFLD)

Non-alcoholic fatty liver disease (NAFLD) is emerging as a prominent condition in Western countries. In this review we describe the characteristics and current treatments of NAFLD and discuss opportunities for developing new therapeutic management approaches, with a particular emphasis on development of animal studies and in vitro assays for identification of components of natural product medicines. The main manifestation of NAFLD is hepatic lipid accumulation in the form of lipid droplets (LDs), known as hepatic steatosis (fatty liver). Current treatments for NAFLD generally aim to reduce triglyceride (TG) accumulation, often utilizing thiazolidinedines (TZDs) and fibrates, which are known to lower TG levels in hyperlipidemia, diabetes and metabolic syndrome. Both of these compounds act through activation of nuclear receptors of the Peroxisome Proliferator-Activated Receptor (PPAR) family, thereby activating genes involved in triglyceride metabolism. Thus treatment using natural PPAR α and PPAR γ ligands, such as polyunsaturated fatty acids (PUFA), has also been considered. Alternatively, natural medicines for the treatment of NAFLD have a long and successful history of controlling disease without prominent side effects. However, active compounds in natural medicine responsible for lowering hepatic TG levels are yet poorly characterized. This points to the need for medium-high throughput screening assays to identify active components within natural herbs. As outlined in this review, the quantification of the size and number of lipid droplets could provide an opportunity to screen compound libraries derived from natural medicine for their potential to reduce NAFLD.     

尿酸在非酒精性脂肪性肝病形成的作用

非酒精性脂肪性肝病（nonalcoholic fatty liver disease, NAFLD）作为世界上最常见的慢性肝病之一,一直是研究的热点。NAFLD与肥胖及相关代谢紊乱密切相关。高尿酸血症或高血清尿酸水平是发生在肥胖者身上常见的代谢异常。流行病学研究证实了血清尿酸水平与非酒精性脂肪肝显著相关,而黄嘌呤氧化酶（xanthine oxidase, XO）是控制尿酸合成的关键酶。本文着重对尿酸及控制其合成的限速酶XO在NAFLD形成中的作用进行综述;阐述了尿酸与代谢综合症（metabolic syndrome, MS）相关疾病之间的关系,如胰岛素抵抗、糖尿病和高血脂;最后介绍了XO抑制剂在各种疾病治疗中的应用。     

肝脏脂代谢与非酒精性脂肪肝研究进展

非酒精性脂肪肝（NAFLD）是指除酒精和其他明确的损伤肝脏的因素所致的,以弥漫性肝细胞肥大、泡性肝脂肪变性为主要特征的临床病理综合征。近年来,非酒精性脂肪肝患者数量在逐年升高,已严重威胁人类健康。本文主要从肝脏脂代谢的过程讨论了肝脏脂代谢和非酒精性脂肪肝的关系的研究进展。     

Current pharmacological treatment of nonalcoholic fatty liver

Nonalcoholic fatty liver disease (NAFLD) is a frequent and potentially progressive chronic liver disease that occurs in subjects who do not abuse alcohol. NAFLD is often associated with obesity, metabolic syndrome and insulin resistance and its more aggressive form, nonalcoholic steatohepatitis (NASH) is a major cause of cryptogenic cirrhosis. NAFLD/NASH are commonly detected because of elevated serum aminotransferase levels, ultrasonographic fatty liver and, at liver histology, steatosis, inflammation, and occasionally fibrosis that may progress to cirrhosis. No established treatment exists for this potentially serious disorder. Current management of NAFLD/NASH is largely conservative and includes diet regimen, aerobic exercise, and interventions towards the associated metabolic abnormalities. The main concern is therefore to decrease liver steatosis and its progression toward steatohepatitis and fibrosis, and the risk of "cryptogenic" cirrhosis. Among the most promising medications, weight reducing drugs, insulin sensitizers and lipid-lowering agents, antioxidants, bile salts, co-factors increasing the mitochondrial transport of fatty acids are being considered. Among them, thiazolidinediones are the most promising drug family that act by activating PPARgamma nuclear receptors and by regulating both microsomal and peroxisomal lipid oxidative pathways. Pharmacological treatment of obesity and probiotics should be considered as potential therapeutic options. In this review, after summarizing the general background on fatty liver, the most current and attractive pharmacological approaches to the problem of NAFLD/NASH are discussed.     

Present and future therapeutic strategies in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is found in individuals who do not drink or abuse alcohol and represents a significant health burden for the general community. NAFLD is often associated with one or more features of the metabolic syndrome and has potential for evolution towards non-alcoholic steatohepatitis (NASH), the necro-inflammatory form of liver steatosis. The most worrisome evolutive events in a subgroup of NASH patients include advanced liver fibrosis, cirrhosis, and hepatocellular carcinoma. Pathophysiology of NAFLD/NASH is complex, but studies point to a pre-eminent role of oxidative stress and lipid peroxidation in the liver, including early mitochondrial dysfunction. Changes follow an insulin resistance status with a background of a chronic pro-inflammatory status due to an excess of visceral adiposity. Although no established therapy exists for NAFLD/NASH, potential therapeutic approaches are discussed in this review.     

Present and future therapeutic strategies in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is found in individuals who do not drink or abuse alcohol and represents a significant health burden for the general community. NAFLD is often associated with one or more features of the metabolic syndrome and has potential for evolution towards non-alcoholic steatohepatitis (NASH), the necro-inflammatory form of liver steatosis. The most worrisome evolutive events in a subgroup of NASH patients include advanced liver fibrosis, cirrhosis, and hepatocellular carcinoma. Pathophysiology of NAFLD/NASH is complex, but studies point to a pre-eminent role of oxidative stress and lipid peroxidation in the liver, including early mitochondrial dysfunction. Changes follow an insulin resistance status with a background of a chronic pro-inflammatory status due to an excess of visceral adiposity. Although no established therapy exists for NAFLD/NASH, potential therapeutic approaches are discussed in this review.     

Review article: nonalcoholic fatty liver disease and hepatitis C virus--partners in crime

Background Both nonalcoholic fatty liver disease (NAFLD) and chronic hepatitis C (CHC) are frequent causes of chronic liver disease. In recent years, there have been significant revelations as regards the relationship between NAFLD and CHC. Aim To conduct a systematic, evidence‐based review of the epidemiology, pathophysiology and potential treatments of coexistent NAFLD and CHC. Methods The terms such as hepatitis C, fatty liver, NAFLD, nonalcoholic steatohepatitis and steatosis were searched on PubMed up to January 2008. References from selected articles and pertinent abstracts were also included. Results Hepatic steatosis affects up to 80% of patients with CHC and is dependent on both viral and host factors. While insulin resistance (IR) is associated with hepatic steatosis and hepatitis C virus, genotype‐specific pathogenic mechanisms have been identified and are currently the focus of intense investigation in the literature. Clinical implications of concurrent NAFLD, CHC and IR include increased disease progression, elevated risk of hepatocellular carcinoma, and decreased response to antiviral therapy. Conclusions NAFLD and IR are common in patients with CHC virus infection. IR is a driving force in the development of hepatic steatosis. Because of the clinical implications of hepatic steatosis and IR in the setting of CHC, further studies evaluating treatments, which may increase response to antiviral therapy, are needed.     

Advances in the understanding and treatment of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a well recognised form of chronic liver disease that has recently gained greater recognition. Originally described in the late 1950s, NAFLD is currently considered the leading cause of abnormal liver enzyme levels in the US, closely paralleling the increase in obesity and diabetes mellitus. NAFLD has a worldwide distribution, affecting both adults and children, and typically is seen in association with obesity, diabetes, hypertension and hypertriglyceridaemia. Most patients are asymptomatic and usually present with mild elevations in aminotransferases. The natural history of NAFLD is not clearly defined but progression to cirrhosis and end-stage liver disease is well recognised in some patients. The accumulation of hepatic steatosis is thought to occur initially, primarily through hepatic and peripheral insulin resistance, which leads to altered glucose and free fatty acid metabolism. The progression from simple fatty liver to more severe forms of NAFLD (nonalcoholic steatohepatitis and cirrhosis) is much less clear but evidence suggests that oxidative stress may preferentially enhance proinflammatory cytokines, which leads to cellular adaptations and dysfunction followed by development of inflammation, necrosis and fibrosis. Therapeutic modalities remain limited and are largely focused on correcting the underlying insulin resistance or reducing oxidative stress. However, at the present time, there are several limitations to the current potential therapies, mainly because of the lack of large-scale, prospective, randomised studies, as well as clearly defined histological endpoints. Ultimately, the future for potential therapeutic modalities to treat this disease are quite promising, but further research is needed to clearly demonstrate which therapy or therapies will be effective at eliminating fatty liver disease and its potential complications.     

The inhibitory effect of black soybean on hepatic cholesterol accumulation in high cholesterol and high fat diet-induced non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is defined as excess of fat in the liver. We investigated the effects of black soybean on the cholesterol metabolism and insulin resistance of mice fed high cholesterol/fat diets. Mice were randomly allocated into four groups that were fed different diets: the normal cholesterol/fat diet; high cholesterol/fat diets (HCD); and HCD with 1%, and 4% black soybean powder (1B-HCD, and 4B-HCD). Liver total cholesterol and triglyceride concentrations were significantly lower in the black soybean-supplemented groups than that in the HCD group. PCR revealed significantly lower hepatic SREBP2 and HMG-CoA reductase mRNA levels of black soybean-supplemented mice. Real-time PCR revealed significantly higher hepatic ABCA1 mRNA level of black soybean-supplemented mice, which may increase cholesterol efflux. Liver bile acids concentration was significantly high in the 4B-HCD group. Black soybean stimulated secretion of adiponectin, activation of pAMPK, and eliminated free fatty acids in the liver. Black soybean supplementation decreased MDA and nitrate level. The activities of SOD, catalase, and GPx were restored by black soybean supplementation. Our data strongly indicate that black soybean influences the balance between oxidative and antioxidative stress. We suggest that black soybean improves cholesterol metabolism, insulin resistance, and alleviates oxidative damage in NAFLD.     

Bavachinin inhibits cholesterol synthesis enzyme FDFT1 expression via AKT/mTOR/SREBP-2 pathway

Non-alcoholic fatty liver disease (NAFLD) is a progressive and chronic liver disease. No effective drug is currently approved for the treatment of NAFLD. Traditionally it is thought that pathogenesis of NAFLD develops from some imbalance in lipid control, thereby leading to hepatotoxicity and disease development. Squalene synthase (SQS), encoded by FDFT1, is a key regulator in cholesterol synthesis and thus a potential target for the treatment of NAFLD. Here we could identify bavachinin, a component from traditional Chinese medicine Fructus Psoraleae (FP), which apparently protects HepaRG cells from palmitic acid induced death, suppressing lipid accumulation and cholesterol synthesis through inhibition of FDFT1 through the AKT/mTOR/SREBP-2 pathway. Over-expression of FDFT1 abolished bavachinin (BVC) -induced inhibition of cholesterol synthesis. The data presented here suggest that bavachinin acts as a cholesterol synthesis enzyme inhibitor, and might serve as a drug for treating NAFLD in the future.