NASH Target Development Service for Nuclear Transcription Factor

Over the next decade, NASH is projected to be the most common indication for liver transplantation. The nuclear transcription factors have drawn much attention due to the therapeutic potential ability for the treatment of NASH. With years of experience and high-end technologies in target identification for drug discovery, Creative Biolabs provides the world's leading target screening, structural characterization, and functional profiling services for identifying potential drug targets. We are proud to offer the most comprehensive services list for NASH therapy.

Introduction of Nuclear Transcription Factors

Nuclear receptors are a class of recognized therapeutic targets already exploited by the pharmaceutical industry. To aid in the pre-clinical discovery and optimization of novel compounds for the treatment of NASH, modulation of nuclear transcription factors has become a hot research direction in NASH therapy. Several nuclear transcription factors have therapeutic potential for the treatment of NASH, including farnesoid X nuclear receptor (FXR) activators, pregnane X receptor (PXR) activators, and peroxisome proliferator-activated receptors (PPARs) activators.

Farnesoid X Nuclear Receptor (FXR) Activators

Bile-acids (BAs) are the major products of cholesterol catabolism that facilitate the intestinal absorption and transport of dietary lipids. Originally identified as a BAs sensor in enterohepatic tissues, FXR has emerged as a master regulator of lipid and glucose homeostasis and of inflammatory and fibrogenic processes. It has become targets with increasing interests for the biotech and pharma companies because of their roles as master regulators of carbohydrate and lipid metabolism, bile acid homeostasis, inflammation, and fibrosis, all of which may influence NASH development. FXR activation leads to the reduction in serum and hepatic triglyceride levels and also directly inhibits hepatic stellate cell (HSC) activation and hepatic fibrogenesis, and it has several beneficial extrahepatic effects as it reverses adipose tissue dysfunction and decreases gut microbiota induced inflammation.

Fig.1 Regulation of BA synthesis by FXR signaling. (Shapiro, 2018)

Pregnane X Receptor (PXR) Activators

Initially identified as the steroid and xenobiotic sensor, the PXR has been functionally linked to the regulation of various physiologic processes that are associated with lipid metabolism and energy homeostasis. Activated by the antibiotic rifampicin and various plant metabolites, such as hyperforin, guggulipid, colupulone, and isoflavones, PXR's response to specific ligands is species-specific. The PXR is transcriptionally functional in human hepatic stellate cells and their activators inhibit trans-differentiation and proliferation. It is also an important modulator of metabolic and inflammatory pathways in hepatic and extrahepatic tissues and is a potential therapeutic target for NASH.

Peroxisome Proliferator-Activated Receptors (PPARs) Activators

The PPARs belong to a class of nuclear receptors and have three isoforms designated PPARα, PPARδ (also known as PPARβ) and PPARγ. PPARα is expressed ubiquitously but is largely present in the liver. PPARδ is expressed mainly in skeletal muscle and to a lesser degree in adipose tissue and skin. PPARγ is highly expressed in adipose tissue. They induce the expression of numerous genes by functioning as ligand-activated transcription factors. The ligands of several PPARs include serial compounds and endogenous lipids, such as FFAs and eicosanoids. Because of their key role in the transcriptional regulation of glucose and lipid metabolism, PPARs have been investigated as possible therapeutic agents for NASH.

Fig.2 The relationship between PPARs and NASH. (Wang, 2017)

Features

• Seasoned technology
• Reasonable planning and design
• Tailoring the one-stop target identification and validation service
• Pre-made library screening
• High-quality, reliable and cost-effective manner
• 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 needs in NASH services, please feel free to contact us for more details.

References

1. Shapiro, H.; et al. Bile acids in glucose metabolism in health and disease. Journal of Experimental Medicine. 2018, 215(2): 383-396.
2. Wang, N.; et al. Peroxisome proliferator-activated receptors associated with nonalcoholic fatty liver disease. PPAR research. 2017, 2017: 1-8.