Focus on emerging drugs for the treatment of patients with non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD)has become the most common liver disorder in Western countries and is increasingly being recognized in developing nations.Fatty liver disease encompasses a spectrum of hepatic pathology,ranging from simple steatosis to non-alcoholic steatohepatitis,cirrhosis,hepatocellular carcinoma and end-stage liver disease.Moreover,NAFLD is often associated with other metabolic conditions,such as diabetes mellitus type 2,dyslipidemia and visceral obesity.The most recent guidelines suggest the management and treatment of patients with NAFLD considering both the liver disease and the associated metabolic co-morbidities.Diet and physical exercise are considered the first line of treatment for patients with NAFLD,but their results on therapeutic efficacy are often contrasting.Behavior therapy is necessary most of the time to achieve a sufficient result.Pharmacological therapy includes a wide variety of classes of molecules with different therapeutic targets and,often,little evidence supporting the real efficacy.Despite the abundance of clinical trials,NAFLD therapy remains a challenge for the scientific community,and there are no licensed therapies for NAFLD.Urgently,new pharmacological approaches are needed.Here,we will focus on the challenges facing actual therapeutic strategies and the most recent investigated molecules.     

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.     

运动防治非酒精性脂肪性肝病的机制

非酒精性脂肪性肝病(NAFLD)目前已经成为全球流行的慢性肝脏疾病.运动能够改善NAFLD.研究证实,运动能够减轻肝脏脂肪沉积及炎性反应,但其具体机制尚不明确,有待进一步研究.     

Olive oil consumption and non-alcoholic fatty liver disease

The clinical implications of non-alcoholic fatty liver diseases （NAFLD） derive from their potential to progress to fibrosis and cirrhosis. Inappropriate dietary fat intake, excessive intake of soft drinks, insulin resistance and increased oxidative stress results in increased free fatty acid delivery to the liver and increased hepatic triglyceride （TG） accumulation. An olive oil-rich diet decreases accumulation of TGs in the liver, improves postprandial TGs, glucose and glucagon- like peptide-1 responses in insulin-resistant subjects, and upregulates glucose transporter-2 expression in the liver. The principal mechanisms include： decreased nuclear factor-kappa B activation, decreased low- density lipoprotein oxidation, and improved insulin resistance by reduced production of inflammatory cytokines （tumor necrosis factor, interleukin-6） and improvement of jun N-terminal kinase-mediated phosphorylation of insulin receptor substrate-1. The beneficial effect of the Mediterranean diet is derived from monounsaturated fatty acids, mainly from olive oil. In this review, we describe the dietary sources of the monounsaturated fatty acids, the composition of olive oil, dietary fats and their relationship to insulin resistance and postprandial lipid and glucose responses in non-alcoholic steatohepatitis, clinical and experimental studies that assess the relationship between olive oil and NAFLD, and the mechanism by which olive oil ameliorates fatty liver, and we discuss future perspectives.     

Alimentary regimen in non-alcoholic fatty liver disease: Mediterranean diet

Non-alcoholic fatty liver disease(NAFLD)is the most common liver disease worldwide.The mechanisms of the underlying disease development and progression are awaiting clarification.Insulin resistance and obesity-related inflammation status,among other possible genetic,dietary,and lifestyle factors,are thought to play the key role.There is no consensus concerning the pharmacological treatment.However,the dietary nutritional management to achieve weight loss is an essential component of any treatment strategy.On the basis of its components,the literature reports on the effectiveness of the Mediterranean diet in reducing cardiovascular risk and in preventing major chronic diseases,including obesity and diabetes.New evidence supports the idea that the Mediterranean diet,associated with physical activity and cognitive behaviour therapy,may have an important role in the prevention and the treatment of NAFLD.     

Physical activity as a treatment of non-alcoholic fatty liver disease: A systematic review

AIM: To review the effectiveness of exercise as a therapy for nonalcoholic fatty liver disease (NAFLD) and potential benefits in treating insulin resistance and atherosclerosis.METHODS: Medline (EBSCOhost) and PubMed were searched for English-language randomized controlled trials and prospective cohort studies in human adults aged ≥ 18 which investigated the various effects of exercise alone, a combination of exercise and diet, or exercise and diet coupled with behavioral modification on NAFLD from 2010 to Feburary 2015.RESULTS: Eighteen of 2298 available studies were chosen for critical review, which included 6925 patients. Nine (50%) studies were randomized controlled trials. Five (27.8%) studies utilized biopsy to examine the effects of physical activity on hepatic histology. The most commonly employed imaging modality to determine change in hepatic steatosis was hydrogen-magnetic resonance spectroscopy. Only two studies examined the effects of low impact physical activity for patients with significant mobility limitations and one compared the efficacy of aerobic and resistance exercise. No studies examined the exact duration of exercise required for hepatic and metabolic improvement in NAFLD.CONCLUSION: While exercise improved hepatic steatosis and underlying metabolic abnormalities in NAFLD, more studies are needed to define the most beneficial form and duration of exercise treatment.     

Current status,problems, and perspectives of non-alcoholic fatty liver disease research

Non-alcoholic fatty liver disease(NAFLD) is a major chronic liver disease that can lead to liver cirrhosis, liver cancer, and ultimately death. NAFLD is pathologically classified as non-alcoholic fatty liver(NAFL) or non-alcoholic steatohepatitis(NASH) based on the existence of ballooned hepatocytes,although the states have been known to transform into each other. Moreover,since the detection of ballooned hepatocytes may be difficult with limited biopsied specimens, its clinical significance needs reconsideration. Repeated liver biopsy to assess histological NAFLD activity for therapeutic response is also impractical, creating the need for body fluid biomarkers and less invasive imaging modalities. Recent longitudinal observational studies have emphasized the importance of advanced fibrosis as a determinant of NAFLD outcome. Thus,identifying predictors of fibrosis progression and developing better screening methods will enable clinicians to isolate high-risk NAFLD patients requiring early intensive intervention. Despite the considerable heterogeneity of NAFLD with regard to underlying disease, patient age, and fibrosis stage, several clinical trials are underway to develop a first-in-class drug. In this review, we summarize the present status and future direction of NAFLD/NASH research towards solving unmet medical needs.     

Monounsaturated fat decreases hepatic lipid content in non-alcoholic fatty liver disease in rats

AIM： To evaluate the effects of different types of dietary fats on the hepatic lipid content and oxidative stress parameters in rat liver with experimental non-alcoholic fatty liver disease （NAFLD）. METHODS： A total of 32 Sprague-Dawley rats were randomly divided into five groups. The rats in the control group （n = 8） were on chow diet （Group 1）, rats （n = 6） on methionine choline-deficient diet （MCDD） （Group 2）, rats （n = 6） on MCDD enriched with olive oil （Group 3）, rats （n = 6） on MCDD with fish oil （Group 4） and rats （n = 6） on MCDD with butter fat （Group 5）. After 2 mo, blood and liver sections were examined for lipids composition and oxidative stress parameters.
RESULTS： The liver weight/rat weight ratio increased in all treatment groups as compared with the control group. Severe fatty liver was seen in MCDD ＋ fish oil and in MCDD ＋ butter fat groups, but not in MCDD and MCDD ＋ olive oil groups. The increase in hepatic triglycerides （TG） levels was blunted by 30% in MCDD ＋ olive oil group （0.59 ±0.09） compared with MCDD group （0.85 ±0.04, P 〈 0.004）, by 37% compared with MCDD ＋ fish oil group （0.95 ±0.07, P 〈 0.001）, and by 33% compared with MCDD ＋ butter group （0.09 ±0.1, P 〈 0.01）. The increase in serum TG was lowered by 10% in MCDD ＋ olive oil group （0.9 ±0.07） compared with MCDD group （1.05 ±0.06）. Hepatic cholesterol increased by 15-fold in MCDD group [（0.08 ±0.02, this increment was blunted by 21% in MCDD ＋ fish oil group （0.09 ±0.02）]. In comparison with the control group, ratio of long-chain polyunsaturated fatty acids omega-6/omega-3 increased in MCDD ＋ olive oil, MCDD ＋ fish oil and MCDD ＋ butter fat groups by 345-, 30- and 397-fold, respectively. In comparison to MCDD group （1.58 ±0.08）, hepatic MDA contents in MCDD ＋ olive oil （3.3 ±0.6）, MCDD ＋ fish oil （3.0 ±0.4）, and MCDD ＋ butter group （2.9 ±0.36） were increased by 108%, 91% and 87%, respecti     

Fructose consumption as a risk factor for non-alcoholic fatty liver disease

BACKGROUND/AIMS: While the rise in non-alcoholic fatty liver disease (NAFLD) parallels the increase in obesity and diabetes, a significant increase in dietary fructose consumption in industrialized countries has also occurred. The increased consumption of high fructose corn syrup, primarily in the form of soft drinks, is linked with complications of the insulin resistance syndrome. Furthermore, the hepatic metabolism of fructose favors de novo lipogenesis and ATP depletion. We hypothesize that increased fructose consumption contributes to the development of NAFLD. METHODS: A dietary history and paired serum and liver tissue were obtained from patients with evidence of biopsy-proven NAFLD (n=49) without cirrhosis and controls (n=24) matched for gender, age (+/-5 years), and body mass index (+/-3 points). RESULTS: Consumption of fructose in patients with NAFLD was nearly 2- to 3-fold higher than controls [365 kcal vs 170 kcal (p<0.05)]. In patients with NAFLD (n=6), hepatic mRNA expression of fructokinase (KHK), an important enzyme for fructose metabolism, and fatty acid synthase, an important enzyme for lipogenesis were increased (p=0.04 and p=0.02, respectively). In an AML hepatocyte cell line, fructose resulted in dose-dependent increase in KHK protein and activity. CONCLUSIONS: The pathogenic mechanism underlying the development of NAFLD may be associated with excessive dietary fructose consumption.     

Effectiveness of exercise in hepatic fat mobilization in nonalcoholic fatty liver disease: Systematic review

AIM: To investigate the efficacy of exercise interventions on hepatic fat mobilization in non-alcoholic fatty liver disease(NAFLD) patients.METHODS: Ovid-Medline, Pub Med, EMBASE and Cochrane database were searched for randomized trials and prospective cohort studies in adults aged ≥ 18 which investigated the effects of at least 8 wk of exercise only or combination with diet on NAFLD from 2010 to 2016. The search terms used to identify articles, in which exercise was clearly described by type, duration, intensity and frequency were: "NASH", "NAFLD", "nonalcoholic steatohepatitis", "non-alcoholic fatty liver disease", "fat", "steatosis", "diet", "exercise", "MR spectroscopy" and "liver biopsy". NAFLD diagnosis, as well as the outcome measures, was confirmed by either hydrogen-magnetic resonance spectroscopy(H-MRS) or biopsy. Trials that included dietary interventions along with exercise were accepted if they met all criteria. RESULTS: Eight studies met selection criteria(6 with exercise only, 2 with diet and exercise with a total of 433 adult participants). Training interventions ranged between 8 and 48 wk in duration with a prescribed exercise frequency of 3 to 7 d per week, at intensities between 45% and 75% of VO2 peak. The most commonly used imaging modality was H-MRS and one study utilized biopsy. The effect of intervention on fat mobilization was 30.2% in the exercise only group and 49.8% in diet and exercise group. There was no difference between aerobic and resistance exercise intervention, although only one study compared thetwo interventions. The beneficial effects of exercise on intrahepatic triglyceride(IHTG) were seen even in the absence of significant weight loss. Although combining an exercise program with dietary interventions augmented the reduction in IHTG, as well as improved measures of glucose control and/or insulin sensitivity, exercise only significantly decreased hepatic lipid contents.CONCLUSION: Prescribed exercise in subjects with NAFLD reduces IHTG independent of dietary intervention. Diet and exercise was more effective than exercise alone in reducing IHTG.     

Management of non-alcoholic fatty liver disease in 2015

There is no single pharmacologic therapy that has been approved to treat nonalcoholic fatty liver disease in the general population. The backbone of therapy currently includes intensive lifestyle modification with established targets for diet and weight loss. The use of unsweetened, unfiltered coffee along with limiting high fructose corn syrup have emerged as beneficial dietary recommendations. The use of empiric oral hypoglycemic agents and vitamin E, however, has not been widely accepted. Developing bariatric surgical techniques are promising, but additional studies with long-term follow up are needed before it can be widely recommended. Finally, liver transplantation is an increasingly frequent consideration once complications of end-stage disease have developed. The future treatment of those with nonalcoholic fatty liver disease will likely involve a personalized approach. The importance of the gut microbiome in mediating hepatocyte inflammation and intestinal permeability is emerging and may offer avenues for novel treatment. The study of anti-fibrotic agents such as pentoxifylline and FXR agonists hold promise and new pathways, such as hepatocyte cannabinoid receptor antagonists are being studied. With the incidence of obesity and the metabolic syndrome increasing throughout the developed world, the future will continue to focus on finding novel agents and new applications of existing therapies to help prevent and to mediate the progression of nonalcoholic fatty liver disease.     

CEUS and Fibroscan in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis

AIM: To determine intra-hepatic blood flow and liver stiffness in patients with non-alcoholic fatty liver disease(NAFLD) and non-alcoholic steatohepatitis (NASH) using contrast-enhanced ultrasound and fibroscan.METHODS: This prospective study included 15 patients with NAFLD, 17 patients with NASH and 16 healthy controls.In each patient, real-time ultrasound was used to locate the portal vein (PV) and the right liver lobe, and 5 mL of SonoVue? was then injected intravenous in a peripheral vein of the left arm over a 4-s span. Digital recording was performed for 3 min thereafter. The recording was subsequently retrieved to identify an area of interest in the PV area and in the right liver parenchyma(LP) to assess the blood flow by processing the data using dedicated software (Qontrast?, Bracco, Italy).The following parameters were evaluated: percentage of maximal contrast activity (Peak%), time to peak (TTP, s), regional blood volume (RBV, cm3), regional blood flow (RBF, cm3/s) and mean transit time (MTT, s).At 24-48 h post-injection, liver stiffness was evaluated using Fibroscan and measured in kPa. The statistical evaluation was performed using Student’s t test.RESULTS: In the PV, the Peak%, RBV and RBF were significantly reduced in the NAFLD and NASH patientscompared with the controls (Peak%: NAFLD 26.3 ± 6.6,NASH 28.1 ± 7.3 vs controls 55.8 ± 9.9, P 0.001;RBV: NAFLD 4202.3 ± 3519.7, NASH 3929.8 ± 1941.3vs controls 7473 ± 3281, P 0.01; RBF: NAFLD 32.5± 10.8, NASH 32.7 ± 12.1 vs controls 73.1 ± 13.9, P 0.001). The TTP in the PV was longer in both patient groups but reached statistical significance only in the NASH patients compared with the controls (NASH 79.5± 37.8 vs controls 43.2 ± 30, P 0.01). In the LP,the Peak%, RBV and RBF were significantly reduced in the NAFLD and NASH patients compared with the controls (Peak%: NAFLD 43.2 ± 7.3, NASH 41.7 ± 7.7 vs controls 56.6 ± 6.3, P 0.001; RBV: NAFLD 4851.5± 2009, NASH 5069.4 ± 2292.5 vs controls 6922.9 ±2461.5, P 0.05; RBF: NAFLD 55.7 ± 10.1, NASH 54.5 ± 12.1 vs controls 75.9 ± 10.5, P 0.001). The TTP was longer in both patient groups but did not reach statistical significance. The MTT in both the PV and LP in the NAFLD and NASH patients was not different from that in the controls. Liver stiffness was significantly increased relative to the controls only in the NASH patients(NASH: 6.4 ± 2.2 vs controls 4.6 ± 1.5, P 0.05).CONCLUSION: Blood flow derangement within the liver present not only in NASH but also in NAFLD suggests that a vascular flow alteration precedes liver fibrosis development.     

Indian patients with human immunodeficiency virus infection have high prevalence but mild severity of non-alcoholic fatty liver disease

Background and aimsAntiretroviral therapy (ART) has substantially decreased AIDS-related mortality. Non-AIDS related diseases like chronic liver disease are becoming more frequent in people living with HIV-AIDS (PLHA). Non-alcoholic fatty live disease (NAFLD) is a common etiology of liver disease in the general population. Our aim was to analyse the prevalence and risk factors of NAFLD in Indian PLHA.MethodsOne hundred consecutive adults (age:36.89 ± 10.4 years, males:65%) with HIV infection were prospectively enrolled. Patients with significant alcohol intake, Hepatitis B or Cco-infection, other liver disease, malignancy or HIV stage IV were excluded. Hepatic steatosis was assessed using hepatobiliary ultrasoundand controlled attenuation parameter (CAP). Fibrosis was assessed non-invasively using FIB-4, NAFLD fibrosis score (NFS) and liver stiffness measurement (LSM). Metabolic and HIV-related risk factors were compared between PLHA with and without NAFLD.ResultsPrevalence of NAFLD using CAP was 60%. Among patients with NAFLD, 27 (45%) were lean. Majority had mild-moderate steatosis. Advanced fibrosis was present in 1 (1.67%) and 4 (6.67%) patients using NFS and LSM and none using FIB-4. PLHA with NAFLD were more likely to be overweight or obese (OR = 4.21,p = 0.002) with a higher proportion of abdominal obesity (OR:25.26,p = 0.001). Other metabolic comorbidities, duration of HIV infection, duration and type of ART, CD4-count or HIV-stagewere not significantly different among PLHA with or without NAFLD.ConclusionPrevalence of NAFLD among Indian PLHA is high although most have mild disease. Almost half of these patients are lean. HIV-related factors do not impact the risk of NAFLD.     

Role of diet on non-alcoholic fatty liver disease: An updated narrative review

The purpose of this article review is to update what is known about the role of diet on non-alcoholic fatty liver disease (NAFLD). NAFLD is the most common cause of chronic liver disease in the developed world and is considered to be a spectrum, ranging from fatty infiltration of the liver alone (steatosis), which may lead to fatty infiltration with inflammation known as non alcoholic steatohepatitis While the majority of individuals with risk factors like obesity and insulin resistance have steatosis, only few people may develop steatohepatitis. Current treatment relies on weight loss and exercise, although various insulin-sensitizing medications appear promising. Weight loss alone by dietary changes has been shown to lead to histological improvement in fatty liver making nutrition therapy to become a cornerstone of treatment for NAFLD. Supplementation of vitamin E, C and omega 3 fatty acids are under consideration with some conflicting data. Moreover, research has been showed that saturated fat, trans-fatty acid, carbohydrate, and simple sugars (fructose and sucrose) may play significant role in the intrahepatic fat accumulation. However, true associations with specific nutrients yet to be clarified.     

Bariatric surgery in patients with non-alcoholic fatty liver disease-from pathophysiology to clinical effects

Non-alcoholic fatty liver disease(NAFLD) is increasingly recognized as a significant liver disease,and it covers the disease spectrum from simple steatosis with a risk of development of non-alcoholic steatohepatitis(NASH) to fibrosis,subsequent cirrhosis,end-stage liver failure,and liver cancer with a potential need for liver transplantation.NAFLD and NASH are closely related to obesity,metabolic syndrome,and type 2 diabetes(T2 D).The role of gut hormones,especially glucagon-like peptide 1(GLP-1),is important in NAFLD.Bariatric surgery has the potential for inducing great weight loss and may improve the symptoms of metabolic syndrome and T2 D.Recent data demonstrated significant effects of bariatric surgery on GLP-1 and other gut hormones and important lipid metabolic and inflammatory abnormalities in the pathophysiology of NAFLD.Therefore,bariatric surgery may reverse the pathological liver changes in NAFLD and NASH patients.In the present review,we describe NAFLD and NASH pathophysiology and the primary effects of bariatric surgery on metabolic pathways.We performed a systematic review of the beneficial and harmful effects and focused on changes in liver disease severity in NAFLD and NASH patients.The specific focus was liver histopathology as assessed by the invasive liver biopsy.Additionally,we reviewed several non-invasive methods used for the assessment of liver disease severity following bariatric surgery.     

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.     

CD36 palmitoylation disrupts free fatty acid metabolism and promotes tissue inflammation in non-alcoholic steatohepatitis

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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.