NASH Target Development Service for Lipotoxicity

NASH is predicted to be the most common cause of liver transplantation in the future. Up to now, there has no drug been approved by FDA for NASH treatment. In order to discover the more effective drug, Creative Biolabs has established a world-leading technological platform, target identification for drug discovery, which allows to providing target screening, structural characterization, and functional profiling services for global clients. Currently, increasing studies have reported lipotoxicity may function as an essential role in the progression of NASH. Thus Creative Biolabs, as a leader in drug discovery, is capable of offering the best drug discovery against lipotoxicity and improving NASH therapy.

Introduction of Lipotoxicity

One of the most common symptoms of NASH is over-accumulation of lipids in the liver. Recently, increasing data suggest that the progression from steatosis to NASH may not be determined by the number of triglycerides in the liver but by the accumulation of lipotoxic intermediates in triglyceride synthesis and/or lipolysis. Several lipid metabolites such as free cholesterol, phospholipids (such as ceramides and sphingolipids) and diacylglycerol (DAG) are accumulated in the liver, which are associated with liver cell damage, inflammation and different degrees of scarring or fibrosis. All of these suggest that the lipotoxic intermediates can be regarded as potential therapeutic targets for NASH.

SREBP2 Inhibitors

A number of studies reveal that the free-cholesterol accumulation in the liver may be involved in the pathogenesis of NASH. Removing toxic cholesterol from liver cells may be a potential therapeutic strategy for NASH. In mammals, the nuclear transcription factor SREBP2 (sterol regulatory element-binding protein 2) is a major regulator for intracellular cholesterol homeostasis. It is associated with cholesterol synthesis, uptake, secretion. Hence SREBP2 inhibitors may be the promising strategy for NASH treatment.

Fig.1 SREBP-regulated lipid metabolism. (Shimano, 2017)

Ceramide Depletion

Ceramide is a simple sphingolipid consisting of sphingosine and a fatty acid. Clinical and laboratory studies have suggested that intracellular ceramide accumulation is associated with the pathogenesis of NASH through a variety of mechanisms, including disruption of calcium homeostasis in the endoplasmic reticulum (ER), induction of insulin resistance, activation of nucleotide oligomerization domain (NOD)-, leucine-rich repeat (LRR)- and pyrin domain-containing 3 (NLRP3) inflammasome, and impairment of autophagy. Therefore, reducing cellular ceramide accumulation may be a potential strategy to improve liver disease and relieve the metabolic disturbances.

Fig.2 Ceramide synthesis and the pathogenesis of non-alcoholic steatohepatitis. (Musso, 2016)

DAG O-Acyltransferase (DGAT) Inhibitors

There are two isoforms in DGAT, DGAT1 and DGAT2. DGAT1 is expressed in skeletal muscle, skin, intestine, and testes, with lower levels in the liver and adipose tissue. A small-molecule DGAT1 inhibitor, pradigastat, is approved for the treatment of familial chylomicronaemia syndrome, has been indicated to improve hepatic steatosis in a small randomized clinical trial that enrolled patients with NAFLD. DGAT2 is expressed mainly in the liver and adipose tissue where it regulates lipid metabolism. The high levels of DGAT2 are associated with significant hepatic steatosis and adiposity and insulin resistance. Currently, many studies have been conducted to evaluate the efficacy and safety of DGAT2 inhibitors (such as lipid-lowering agent niacin, mangiferin, indolyl acrylamide derivatives) in the treatment of NASH and associated metabolic disorders.

Fig.3 DGAT2 and DGAT1 act in series. (Zammit, 2013)

Tumour Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)-Receptor (TRAIL-R) Inhibitors

TRAIL-R is a receptor for a cytokine TRAIL. The binding of TRAIL and TRAIL-R could cause apoptosis primarily in tumor cells. TRAIL and TRAIL-R have been used as the targets for cancer therapy. Furthermore, the high expression of TRAIL and TRAIL-R play a key role in the NASH pathogenesis. In a dietary mouse model of NASH, TRAIL-R deletion could exert a protective role in liver diseases through relieving many aspects including steatosis, hepatocyte apoptosis, macrophage associated inflammation, and fibrosis.

Fig.4 Schematic illustrating the role of TRAIL in NASH. (Hirsova, 2017)

JNK Inhibitors

JNK (c-Jun-N-terminal Kinase) is a member of mitogen-activated protein kinase (MAPK) family which can be activated by diverse stimuli such as reactive oxygen species (ROS), pathogens, toxins, endoplasmic reticulum stress, free fatty acids, and cytokines. Upon activation, JNK can regulate multiple biologic events through the transcription factor AP1 (activator protein-1) and transcription-independent control of effector molecules. In the liver, JNK signaling can regulate cell death and survival, differentiation, proliferation, ROS accumulation, metabolism, insulin signaling, and carcinogenesis. Moreover, activated JNK signaling can induce insulin resistance and hepatocyte apoptosis, leading to the progression of NASH in animal model. These data suggest that the blocking of JNK signaling may be a potential therapeutic strategy for NASH. A small molecule apoptosis signal-regulating kinase 1 (ASK1) inhibitor, blocking ASK1-JNK axis, has been shown to reduce hepatic steatosis and fibrosis in diet induced NASH model.

Fig.5 High fat diet induced JNK activation in hepatocytes, Kupffer cells and adipocytes in the development of NAFLD and NASH. (Win, 2018)

Features

• World-leading technological platform
• Extensively experienced in drug discovery
• High-quality and low-cost service
• Best after-sale service

Creative Biolabs is one of the well-recognized experts who are professional in disease target development for a broad range of project objectives. With years of experience, we can offer high-quality target construction and custom target screening services to meet our clients’ demands precisely. Particularly, our services also involve antibody development (e.g. Phage Display & Antibody Library Services, Antibody Analysis Services, Antibody Engineering Services) or the one-stop service of drug discovery. If you have any special need in NASH services, please feel free to contact us for more details.

References

1. Shimano, H.; Sato, R. SREBP-regulated lipid metabolism: convergent physiology-divergent pathophysiology. Nature Reviews Endocrinology. 2017.
2. Musso, G.; et al. Non-alcoholic steatohepatitis: emerging molecular targets and therapeutic strategies. Nature Reviews Drug Discovery. 2016, 15(4): 249-74.
3. Zammit, V. A. Hepatic triacylglycerol synthesis and secretion: DGAT2 as the link between glycaemia and triglyceridaemia. Biochemical Journal. 2013, 451(1): 1-12.
4. Hirsova, P.; et al. TRAIL deletion prevents liver inflammation but not adipose tissue inflammation during murine diet-induced obesity. Hepatology Communications. 2017, 1(7): 648-662.
5. Win, S.; et al. New insights into the role and mechanism of c-Jun-N-terminal kinase signaling in the pathobiology of liver diseases. Hepatology. 2018, 67(5): 2013-2024.

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