Current Drug Targets - Volume 16, Issue 12, 2015

This review addresses two major functions of apolipoprotein (apo) A5 including (1) its role in maintaining normal plasma levels of circulating triglyceride (TG) and (2) its role as a component of hepatic lipid droplets. ApoA5 is synthesized solely in the liver and circulating concentrations are extremely low. In the plasma, ApoA5 associates with TG-rich lipoproteins and enhances TG hydrolysis and remnant lipoprotein clearance. ApoA5 loss-of-function single nucleotide polymorphisms are associated with reduced lipolysis, poor remnant clearance and concomitantly, hypertriglyceridemia. Although there have been substantial breakthroughs in understanding pathophysiology associated with secreted ApoA5, there is a paucity of knowledge on the functionality of intracellular ApoA5. However, recent studies indicate that overexpression of intracellular ApoA5 is positively associated with accumulation of TG-rich lipid droplets in hepatocytes. It is thought that ApoA5 may have a causal role in non-alcoholic fatty liver disease (NAFLD) and thus, may serve as a target for developing therapeutics for NAFLD.

The liver is essential for the control of glucose and lipid metabolism. Excessive accumulation of fat in the liver disturbs its function and leads to the development of fatty liver diseases. The nonalcoholic fatty liver disease (NAFLD) is a common type of fatty liver disease found in patients who have not consumed significant amount of alcohol. Multiple factors and cell types contribute to the development and progression of NAFLD. Diets contain macronutrients with energy and micronutrients with regulatory roles. As an essential micronutrient, vitamin A (VA), plays critical roles in various physiological functions including the regulation of glucose and lipid homeostasis in the liver. The body’s VA is mainly stored in quiescent hepatic stellate cells (HSCs) in the liver. Hepatocytes actively metabolize VA, and change glucose and lipid metabolism in response to VA metabolites. Interestingly, the activated HSCs lose their VA content and contribute to the NAFLD progression. Significant number of studies have been conducted to investigate the link between VA metabolism and NAFLD development. This review is to summarize current literatures that discuss the changes of VA metabolism occurring locally between hepatocytes and HSCs, and intracellularly in hepatocytes during the course of NAFLD development. It appears that factors derived from HSCs and hepatocytes mutually affect each other, which contributes to NAFLD development. Additionally, this review discusses the potential mechanism by which excessive VA metabolism increases lipogenesis and contributes to fat accumulation in hepatocytes. It offers potential future directions for the study of the role of VA metabolism in the NAFLD development.

Non-alcoholic fatty liver disease (NAFLD) is histologically characterized by the aberrant accumulation of lipid droplets in the liver, which is positively correlated with insulin resistance. Within the spectrum of this disease, patients can develop hepatitis and cirrhosis; i.e., non-alcoholic steatohepatitis (NASH). The mechanisms responsible for the progression of NAFLD are not fully understood. Triacylglycerol (TAG), which is mainly found in lipid droplets, is currently considered to act as a buffer against the accumulation of non-TAG toxic lipid species. In line with this, recent studies have revealed that insulin resistance is driven by the accumulation of phosphatidic acid and diacylglycerol in hepatocytes and that cholesterol-overloaded stellate cells are associated with fibrosis in the liver. Therefore, it is important to identify the toxic lipid species that contribute to NAFLD progression in order to clarify the pathogenesis of NASH and find novel targets for its treatment. In this review, we divided lipids into five classes; i.e., into fatty acyls, glycerophospholipids, glycerolipids, sphingolipids, and sterol lipids, and described their molecular structures, distributions, and metabolism under physiological conditions, as well as the contributions they make to the progression of NAFLD.

Nonalcoholic fatty liver disease (NAFLD) represents a broad spectrum of histological abnormalities with clinical presentations ranging from hepatic steatosis to nonalcoholic steatohepatitis (NASH). Some NAFLD patients may progress to cirrhosis and ultimately hepatocellular carcinoma (HCC). Hepatic steatosis, the hallmark of NAFLD, is defined by the accumulation of triglycerides (TGs) in more than 5% of the hepatocytes. NASH is characterized by inflammation along with variable degrees of fibrosis in addition to steatosis. NAFLD has been considered to be the hepatic manifestation of metabolic syndrome (MS), as it is frequently associated with MS conditions such as insulin resistance (IR) and obesity. Hepatic steatosis mainly results from disrupted homeostasis of lipid metabolism in the setting of IR. Although the mechanism underlying the progression from steatosis to NASH is still not fully elucidated, mounting evidence has suggested oxidative stress (OS) to be a key driving force. Elevated OS has been well documented in NAFLD patients. OS can cause direct damages to lipid, protein, and DNA molecules and trigger the inflammatory and fibrogenesis signaling pathways, which promotes the progression from steatosis to NASH. OS may also have various effects on antioxidant defense mechanisms. Overproduced reactive oxygen species (ROS) may directly deplete antioxidant molecules such as glutathione (GSH) and inhibit the activities of antioxidant enzymes such as superoxide dismutase (SOD). ROS may also induce the expression of antioxidant genes to counteract the OS effects. The aim of this review is to discuss oxidative stress and antioxidant mechanisms in NAFLD.

Obesity is a primary risk factor for the development of non-alcoholic fatty liver disease (NAFLD). NAFLD, the most common chronic liver disease in the world, represents a spectrum of disorders that range from steatosis (NAFL) to steatohepatitis (NASH) to cirrhosis. It is anticipated that NAFLD will soon surpass chronic hepatitis C infection as the leading cause for needing liver transplantation. Despite its clinical and public health significance no specific therapies are available. Although the etiology of NAFLD is multifactorial and remains largely enigmatic, it is well accepted that inflammation is a central component of NAFLD pathogenesis. Despite the significance, critical immune mediators, loci of immune activation, the immune signaling pathways and the mechanism(s) underlying disease progression remain incompletely understood. Recent findings have focused on the role of Interleukin 17 (IL-17) family of proinflammatory cytokines in obesity and pathogenesis of obesity-associated sequelae. Notably, obesity favors a Th17 bias and is associated with increased IL-17A expression in both humans and mice. Further, in mice, IL-17 axis has been implicated in regulation of both obesity and NAFLD pathogenesis. However, despite these recent advances several important questions require further evaluation including: the relevant cellular source of IL-17A production; the critical IL- 17RA-expressing cell type; the critical liver infiltrating immune cells; and the underlying cellular effector mechanisms. Addressing these questions may aid in the identification and development of novel therapeutic targets for prevention of inflammation- driven NAFLD progression.

Non-alcoholic fatty liver disease (NAFLD) is a challenge not only due to its rising prevalence but also, and perhaps more importantly, due to the lack of sustainable treatment options. Intestinal microbiota are thought to participate in the development and progression of NAFLD and their manipulation is, hence, being investigated as a treatment aim. This review summarizes the involvement of intestinal microbiota in the pathogenesis on NAFLD. In addition, we synthesize the results of the most recent animal and human studies aimed at treating dysbiosis seen in patients with NAFLD. Lastly, we review the evidence regarding the efficacy of manipulating short chain fatty acid and bile acid signaling in the treatment of NAFLD.

The liver is unique in that it is able to regenerate. This regeneration occurs without formation of a scar in the case of non-iterative hepatic injury. However, when the liver is exposed to chronic liver injury, the purely regenerative process fails and excessive extracellular matrix proteins are deposited in place of normal liver parenchyma. While much has been discovered in the past three decades, insights into fibrotic mechanisms have not yet lead to effective therapies; liver transplant remains the only cure for advanced liver disease. In an effort to broaden the collection of possible therapeutic targets, this review will compare and contrast the liver wound healing response to that found in two types of wound healing: scarless wound healing of fetal skin and oral mucosa and scar-forming wound healing found in adult skin. This review will examine wound healing in the liver and the skin in relation to the role of humoral and cellular factors, as well as the extracellular matrix, in this process. While several therapeutic targets are similar between fibrotic liver and adult skin wound healing, others are unique and represent novel areas for hepatic anti-fibrotic research. In particular, investigations into the role of hyaluronan in liver fibrosis and fibrosis resolution are warranted.

Non-alcoholic fatty liver disease (NAFLD) is a chronic disorder of lipid and carbohydrate metabolism and is often associated with endoplasmic reticulum stress, energy homeostasis dysregulation, and inflammation at cellular and molecular levels. Use of currently available anti-hyperlipidemia, hypoglycemia, or anti-inflammation drugs to treat NAFLD has not achieved desirable outcomes. A growing attention thus has been paid towards natural products as an alternative means in treating NALFD. Some of the natural products apparently possess the properties of ameliorating symptoms of NAFLD through restoration of lipid and carbohydrate metabolism and energy homeostasis. Data from recent animal and human studies concerning the use of natural products in the treatment of NAFLD are analyzed, and the potential underlying mechanisms are discussed.

The superfamily of human ATP-binding cassette (ABC) transporters comprises seven subfamilies (ABCA to G) with 48 members. In addition to their profound physiological and pharmacological functions, ABC transporters play important roles in instigating multidrug resistance (MDR) in cancer by mediating the efflux of many anticancer drugs, particularly, ABCB1, ABCG2 and ABCC subfamily members. Previous development of ABCB1 transporter inhibitors has provided insights into seeking novel strategies in developing new classes of compound that inhibit ABCB1 and other MDRrelated ABC transporters. We herein review and evaluate current evidence in this area, with an emphasis on experimental and investigational agents that are under preclinical and clinical tests, including tyrosine kinase inhibitors, natural products, microRNAs and novel chemical entities. New strategies targeting ABC transporters in cancer stem cells and future perspectives in this field are also discussed.

Accumulation of toxic lipids is the most common etiology of insulin resistance in type 2 diabetes and associated metabolic disorders such as obesity and non-alcoholic fatty liver disease. Understanding of the underlying mechanisms has revealed various opportunities to target key regulators in lipid metabolic pathways for the treatment of metabolic diseases. Here, we review the discovery and development of potential anti-diabetic drugs with primary effects on cellular targets leading to reductions of intracellular lipids in key organs. We will particularly focus on AMPK, SIRT1, PGC-1α, SREBP-1c, ChREBP, ACC, PPARs and HSPs which either stimulate in fatty acid oxidation (energy expenditure) or inhibit de novo lipogenesis.

MicroRNAs (miRNAs) are small single stranded non coding RNA molecules (~22 nucleotides) which impede protein production by directly interacting with 3’untranslated regions of the target mRNAs. Interestingly, miR-200c is often dysregulated in various cancers that normally exhibits tumor suppressive behavior by blocking epithelial to mesenchymal transition (EMT) of cancer cells. However, elevation of miR-200c in various cancer tissues contradicts the tumor suppressive role of this microRNA. This review addresses the molecular mechanisms involved in the regulation of the endogenous level of miR-200c in various cancers such as breast, ovarian, prostate, endometrial, lungs, colon, pancreatic, etc. and its differential role in regulation of proliferation and EMT phenotype of cancer cells. Further, this review discusses whether abnormal level of miR-200c in cancer tissues or in blood circulation can be used as a biomarker. Importantly, how the level of miR-200c can be used to predict the effectiveness of the cancer therapy is also discussed. Accumulating evidences suggest that use of miR-200c alone may not be sufficient for treatment of cancer patients, but the combination of miR-200c with an anti-proliferating drug could be a better choice to prevent invasiveness of cancers as well as tumor growth both in primary and in metastatic sites. This article also proposes that the tumor microenvironment may have a role in influencing epigenetic silencing of miR-200c expression.