Pharmacological management of nonalcoholic fatty liver disease in type 2 diabetes

Introduction: The prevalence of nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes (T2D) is high and it is associated with poor prognosis. Hepatic steatosis results as a consequence of excessive hepatic lipid accumulation which correlates with insulin resistance and lipotoxicity, with subsequent oxidative stress, inflammation, apoptosis and fibrosis.

Areas covered: This article presents the main pathophysiologic mechanisms and currently available drugs evaluated for their therapeutic effects on NAFLD/nonalcoholic steatohepatitis (NASH) and drugs under development that target relevant pathogenetic pathways. However, to date there is no particular drug approved for treatment of NAFLD in patients with T2D.

Expert commentary: Early recognition and intervention are essential to ameliorate disease progression. Specific recommendations are still needed for NAFLD/NASH screening and diagnosis and therapeutic algorithm in patients with T2D. Lifestyle optimization with significant weight loss is a key intervention in patients with NAFLD and T2D. Pioglitazone, liraglutide, vitamin E, OCA and pentoxifylline have proven some histological improvements in NASH and omega 3-PUFAs were shown to decrease liver fat, but no specific recommendation can be made for treatment of NASH. Perhaps a combination of agents that target different pathogenic pathways are needed to better control disease progression, but more robust evidence for these agents is still needed.     

Variations in ATP-binding cassette transporter regulation during the progression of human nonalcoholic fatty liver disease

Transporters located on the sinusoidal and canalicular membranes of hepatocytes regulate the efflux of drugs and metabolites into blood and bile, respectively. Changes in the expression or function of these transporters during liver disease may lead to a greater risk of adverse drug reactions. Nonalcoholic fatty liver disease (NAFLD) is a progressive condition encompassing the relatively benign steatosis and the more severe, inflammatory state of nonalcoholic steatohepatitis (NASH). Here, we present an analysis of the effect of NAFLD progression on the major ATP-binding cassette (ABC) efflux transport proteins ABCC1-6, ABCB1, and ABCG2. Human liver samples diagnosed as normal, steatotic, NASH (fatty), and NASH (not fatty) were analyzed. Increasing trends in mRNA expression of ABCC1, ABCC4-5, ABCB1, and ABCG2 were found with NAFLD progression, whereas protein levels of all transporters exhibited increasing trends with disease progression. Immunohistochemical staining of ABCC3, ABCB1, and ABCG2 revealed no alterations in cellular localization during NAFLD progression. ABCC2 staining revealed an alternative mechanism of regulation in NASH in which the transporter appears to be internalized away from the canalicular membrane. This correlated with a preferential shift in the molecular mass of ABCC2 from 200 to 180 kDa in NASH, which has been shown to be associated with a loss of glycosylation and internalization of the protein. These data demonstrate increased expression of multiple efflux transporters as well as altered cellular localization of ABCC2 in NASH, which may have profound effects on the ability of patients with NASH to eliminate drugs in an appropriate manner.     

纳米载体在非酒精性脂肪肝药物治疗中的研究进展

非酒精性脂肪肝（non-alcohol fatty liver disease，NAFLD）已成为当前全球最常见的肝病之一，临床表现为肝脂肪变性，并逐步恶化为非酒精性脂肪肝炎（nonalcoholic steatohepatitis，NASH）、肝硬化、肝癌等末期肝病。目前治疗NAFLD的药物主要包括保肝药物、胰岛素增敏剂、降脂药、抗氧化剂等，但治疗效果尚未满足要求。纳米载体是纳米医学的重要组成部分，具有增加药物溶解性、控制药物释放、促进口服吸收、提高药物治疗效果和降低药物毒性等优势，在NAFLD药物治疗中具有较大的应用潜力，有待深入研究。     

ω-3多不饱和脂肪酸治疗非酒精性脂肪性肝病的研究进展

非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)是由多种危险因素,如营养过剩、胰岛素抵抗(insulin resistance,IR)及相关代谢紊乱等诱导的慢性肝损伤,是代谢综合征在肝脏的病理表现。其病程的进展表现为非酒精性单纯性脂肪肝(nonalcoholic simple fatty liver,NAFL)、非酒精性脂肪性肝炎(nonalcoholic steatohepatitis,NASH)、脂肪性肝纤维化和脂肪性肝硬化。NAFLD患病率逐年升高,已成为我国最常见的慢性肝病之一。NAFLD的治疗主要为增加运动、健康饮食等基础治疗,药物治疗尚未达成共识。ω-3多不饱和脂肪酸(ω-3 polyunsattrated fatty acids,ω-3PUFAs)具有调节血脂的功能。NAFLD患者ω-3PUFAs水平较低,增加饮食中的ω-3PUFAs可以延缓病情进展,改善肝脏脂代谢的失衡和肝细胞的炎性损伤。本文主要就ω-3PUFAs对NAFLD治疗的研究进展作一综述。     

Promising therapies for treatment of nonalcoholic steatohepatitis

Introduction: Non-alcoholic fatty liver disease (NAFLD) has become the most common etiology for abnormal aminotransferase levels and chronic liver disease. Its growing prevalence is largely linked to the presence of metabolic syndrome, particularly diabetes and insulin resistance. It is estimated that 60–80% of the type 2 diabetic population has NAFLD. NAFLD encompasses a range of conditions ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). A subset of patients with hepatic steatosis progress to NASH, while 15–20% of patients with NASH develop cirrhosis. This progression is thought to be multifactorial, and there are currently no FDA-approved medications for the treatment of NASH.

Areas covered: We review drugs currently in Phase II and III clinical trials for treatment of NAFLD and NASH, including their mechanisms of action, relationship to the pathophysiology of NASH, and rationale for their development.

Expert opinion: The treatment of NASH is complex and necessitates targeting a number of different pathways. Combination therapy, preferably tailored toward the disease stage and severity, will be needed to achieve maximum therapeutic effect. With multiple agents currently being developed, there may soon be an ability to effectively slow or even reverse the disease process in many NAFLD/NASH patients.     

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.     

Toward a biochemical diagnosis of NASH: insights from pathophysiology for distinguishing simple steatosis from steatohepatitis

With the continuing epidemics of obesity and diabetes, nonalcoholic fatty liver disease (NAFLD) has received increased attention. Great efforts are being undertaken to improve the noninvasive diagnosis of NAFLD, with the ultimate goal of optimizing treatment options and clinical outcomes. Research suggests that blood-borne biochemical markers can be used to distinguish simple steatosis from nonalcoholic steatohepatitis (NASH), thus reducing the need of liver biopsy. Future developments in the field of diagnostic biochemistry within the spectrum of NAFLD can make this approach ideal for screening and monitoring purposes. In this review, we provide an overview of the different blood-borne markers which have been recently proposed for differentiating simple steatosis from NASH. We will also consider the practical and statistical issues that seem to be limiting the effective integration of biomarkers into clinical development.     

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.     

Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver condition evolving in a proportion of patients into nonalcoholic steatohepatitis (NASH), an aggressive form of NAFLD associated with increased cardiovascular mortality and significant risk of progressive liver disease, including fibrosis, cirrhosis and hepatocellular carcinoma. At present, no specific therapies for NASH exist. In this review, we examine the evidence supporting activation of the farnesoid X receptor (FXR), a nuclear hormone receptor regulated by bile acids (BAs), for the treatment of NASH. We also discuss the potential of the semi-synthetic BA derivative obeticholic acid (OCA), a first-in-class FXR agonist, as a safe and effective drug to address this significant unmet medical need.     

Non-alcoholic steatohepatitis: what can we learn from animal models?

Non-alcoholic fatty liver disease (NAFLD) is one of the most frequent causes of abnormal liver function and correlates with central adiposity, obesity, insulin resistance, the metabolic syndrome and type 2 diabetes mellitus. The pathological spectrum of NAFLD ranges from fatty liver to non-alcoholic steatohepatitis (NASH), advanced fibrosis, cirrhosis, and even hepatocellular carcinoma. Though NAFLD and NASH are becoming a major public health problem, ethical constraints on obtaining human liver tissue limit the interpretability of the data and the ability to delineate cause and effect from complex, interactive disease pathogenic pathways. Animal models of NASH can provide critical information leading to identify potential drug targets and to understand their molecular mechanisms, and are platforms for compound screening in drug development and for the assessment of novel therapeutic strategies. This review is aimed to offer an updated overview of the nutritional, genetic and pharmacologic animal models of NASH. Though the information derived from these models has clear relevance for the comprehension of the molecular basis of human disease, most of them fail to reproduce the full spectrum of liver pathology and the metabolic context that characterizes human NASH. Consequently, it is necessary to establish animal models that can best mimic the actual etiology, progression, and pathogenesis of the disease, and prove effectiveness for examining and selecting compounds with potential therapeutic benefit in NASH.     

Statins and nonalcoholic fatty liver disease: a bright future?

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease affecting up to 30% of adults in Western countries. NAFLD and mainly nonalcoholic steatohepatitis (NASH) are independent cardiovascular disease (CVD) risk factors; more of these patients are expected to die from CVD rather than from liver disease. The effect of statins on newer risk factors that may influence the pathobiology of liver damage in NASH is considered. These include microparticles, inflammasomes, gut–liver axis abnormalities and dietary lipids. Evidence suggests that statins induce NAFLD/NASH resolution and substantially improve symptom-free survival from CVD to a greater extent than in patients without NAFLD. However, large randomized clinical trials are needed to verify these findings.     

A comprehensive review of recent studies on pharmacokinetics of traditional Chinese medicines (2014–2017) and perspectives

Traditional Chinese medicines (TCMs) have a long history for safely treating human diseases. Unlike western medicine, TCMs usually contain multiple components synergistically and holistically acting on the diseases. It remains a big challenge to represent rationally the in vivo process of multiple components of TCMs for understanding the relationship between administration and therapeutic effects. For years, efforts were always made to face the challenge, and the achievements were obvious. Here, we give an comprehensive overview of the recent investigation progress (from 2015 to 2017, except the part of ‘integrated pharmacokinetics of TCMs’ from 2014 to 2017 and the part of ‘reverse pharmacokinetics in drug discovery from natural medicines’ in 2014) on pharmacokinetics of TCMs, mainly referring to the following six aspects: (1) classical pharmacokinetic studies on TCMs; (2) absorbed components and metabolites identification of TCMs; (3) pharmacokinetic herb–drug interactions and herb–herb interactions with TCMs; (4) integrated pharmacokinetics of TCMs; (5) pharmacokinetic and pharmacodynamic combination studies to dissect the action mechanisms of TCMs; and (6) reverse pharmacokinetics in drug discovery from natural medicines. Finally, based on the insights from the recent progress and our latest efforts, we propose new perspectives on the integrated pharmacokinetics of TCMs.     

Review article: diagnosis and treatment of non-alcoholic fatty liver disease

Background  Non-alcoholic fatty liver disease (NAFLD) is an increasingly prevalent condition affecting adults and children, leading to significant morbidity. It is often associated with the metabolic syndrome, although multiple pathogenetic mechanisms have been suggested. In the coming decades, it promises to be the leading cause of liver disease in industrial countries.
Aim  To provide a comprehensive, updated review of diagnosis and management of NAFLD and to appraise the evolution of new modalities in these areas.
Methods  An Ovid MEDLINE search was performed to identify pertinent original research and review articles. Selected references in these articles were also evaluated.
Results  The diagnosis of hepatic steatosis and steatohepatitis or non-alcoholic steatohepatitis (NASH) is not yet possible without liver biopsy. This is impractical given the large numbers affected by the condition. Current therapy has focused on improving insulin resistance and mediators of inflammation, factors probably associated with disease progression.
Conclusions  There are no proven non-invasive diagnostic modalities to distinguish NAFLD and NASH, but new biomarker panels are approximating the liver biopsy in accuracy. Therapeutic targets of drug development are in early stages, but a multifaceted approach will probably yield several treatment options in the years to come.     

Emerging therapies for the treatment of nonalcoholic steatohepatitis: A systematic review

To describe the mechanism, efficacy, and safety of novel agents that have reached phase 3 clinical trials for the treatment of biopsy-proven nonalcoholic steatohepatitis (NASH). A literature search was conducted using the PRISMA guidelines of MEDLINE databases (1990 to October 2020) with the following MeSH terms: NASH, nonalcoholic liver disease, fatty liver, liver diseases, steatohepatitis, liver fibrosis; combined with obeticholic acid, FXR agonist, cenicriviroc, CCR5 receptor antagonist, elafibranor, PPAR, selonsertib, ASK-1 inhibitor, resmetirom, THR-β receptor, arachidyl amido cholanoic acid (Aramchol™), and SCD-1 modulator. Results were verified via clinicaltrials.gov, Google Scholar, and Google. Articles were included if the medications of interest had ongoing or completed phase 3 trials in biopsy-proven NASH with outcomes directly related to NASH resolution. Eleven studies were identified involving obeticholic acid (OCA), elafibranor, cenicriviroc, Aramchol, and resmetirom. Two agents have reported data from phase 3 trials: OCA and elafibranor. OCA demonstrated safety and efficacy in NASH with a primary end point of improvement or NASH resolution; a new drug approval has been submitted. Elafibranor failed to show efficacy in NASH in the preliminary report from the RESOLVE-IT trial; however, the study is being extended to reassess outcomes. The remaining agents demonstrated positive results in phase 2b studies and have initiated phase 3 trials. With projections for increased prevalence of patients with NASH and the current lack of treatment options, novel agents with targeted mechanisms could potentially change the treatment landscape. The manufacturer of OCA is first to submit a new drug application for the treatment of NASH. These novel agents may fill a pharmacotherapy gap in patients with NASH and possibly prevent progression to advanced liver disease.     

肝脏非实质细胞在非酒精性脂肪性肝炎中的作用研究进展

非酒精性脂肪性肝病是全球最流行的肝脏疾病,其疾病谱包含非酒精性脂肪肝、非酒精性脂肪性肝炎、与非酒精性脂肪性肝炎相关的纤维化、肝硬化和肝细胞癌。非酒精性脂肪性肝炎是非酒精性脂肪性肝病进展性的肝脏病理表征,临床上需要药物治疗或其他治疗方式干预,但目前全球尚无针对非酒精性脂肪性肝炎的药物获批上市。非酒精性脂肪性肝炎发病机制复杂,涉及多种细胞内、细胞间的交互作用以及复杂的分子信号通路。非酒精性脂肪性肝炎治疗是一个尚未被满足的巨大临床需求。综述了肝脏中几种主要的非实质细胞在非酒精性脂肪性肝炎发病中的重要作用,同时探讨了非酒精性脂肪性肝炎药物开发靶点与不同细胞之间的相关性。     

天然免疫与非酒精性脂肪肝病

肝脏中大量的巨噬细胞、自然杀伤细胞(natural killer,NK)、自然杀伤T细胞(natural killer T cell,NKT)等构成了天然免疫系统.这一系统细胞功能紊乱,发生Th-1极化,使促炎症因子产生增多,促进了非酒精性脂肪性肝炎(nonalcoholic steatohepatitis,NASH)的形成;肝脏持续的暴露于这些炎症因子,可以促进多种促纤维化因子产生,但Th-2细胞因子分泌的不足, 使NASH进一步发展为肝硬化的现象却相对比较少见.本文就肝脏天然免疫系统在非酒精性脂肪肝病(nonalcoholic fatty liver disease, NAFLD)中的调节机制作一综述.     

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.