NASH Target Development Service for Energy Homeostasis and Cellular Metabolism

Non-alcoholic steatohepatitis (NASH) is an increasingly prevalent liver pathology that can progress from non-alcoholic fatty liver disease (NAFLD), and it is a leading cause of cirrhosis and hepatocellular carcinoma. Equipped with extensive experience and professional technical team, Creative Biolabs now provides strategies targeting energy homeostasis and cellular metabolism to help you find treatment for NASH.

Strategies Targeting Energy Homeostasis and Cellular Metabolism

• Fibroblast Growth Factor (FGF) Analogues
  The endocrine fibroblast growth factors (FGFs), such as FGF19 and FGF21, are critical regulators of glucose and lipid metabolism. The effects on glucose metabolism and its crucial regulatory role in bile acid homeostasis have endorsed FGF19 and FGF19-inducing strategies. For example, combined mutagenesis of five N-terminal amino acid residues and heparin-binding domains of the wild-type FGF19 yielded a series of chimeric molecules with the ability to modulate glucose regulation. FGF21 is a potent modulator of energy homeostasis and glucose/lipid metabolism. Recombinant FGF21 injection markedly decreases plasma glucose, fatty acid (FA), and triglycerides (TG) in diabetic rhesus monkeys. Treatment with LY2405319, a recombinant variant of FGF21, causes significant improvement in dyslipidemia in obese humans with type 2 diabetes. Studies uncovered a critical role for FGF21 induction in the early stage of methionine-and choline-deficient diet (MCD) model of NASH, which functions to minimize lipid accumulation and ensuing cellular stress in the liver.

Fig.1 Liver-specific FGF19 metabolic actions. (Degirolamo, 2016)

• AMPK Activators
  Activation of adenosine monophosphate (AMP)-activated kinase (AMPK) is modulated by the changes in adenosine triphosphate (ATP), adenosine diphosphate (ADP), and AMP concentrations as well as phosphorylation of upstream AMPK kinase at THR172. Peroxisome proliferator-activated receptor (PPAR)-α agonists such as fenofibrate and PPARγ agonists such as pioglitazone activate AMPK to stimulate the pathways that increase energy production, such as glucose transport and fatty acid oxidation, switching off the pathways that consume energy, such as lipogenesis.
• Carnitine Palmitoyltransferase-1 (CPT-1) Activators
  Carnitine palmitoyltransferase I (CPT-1) is a rate-limiting step in the oxidation of long-chain fatty acids. The activity of CPT-1 is stimulated by the peripheral effect of neurotoxin through the activation of sympathetic nervous system. The decrease of CPT-1 activity severely affects mitochondrial fatty acid oxidation (FAO) and induces the accumulation of free fatty acids (FFA) and triglycerides, lower production of ketone bodies and reduces ATP synthesis.
• Multivesicular Body (MVB) Activators
  Transmembrane BAX inhibitor motif-containing 1 (TMBIM1) is an effective suppressor of steatohepatitis and a previously unknown regulator of the multivesicular body (MVB)-lysosomal pathway. In animal experiments, overexpression of TMBIM1 in the liver effectively inhibited a severe form of NAFLD in mice and NASH progression in monkeys. These findings could lead to the development of promising strategies to treat NASH by targeting MVB regulators to properly orchestrate the lysosome-mediated protein degradation of key mediators of the disease.
• Glucagon-Like Peptide 1 (GLP-1) Agonists
  Dipeptidyl peptidase 4 (DPP-4) inhibitors are effective anti-hyperglycaemic agents by virtue of their ability to inhibit the breakdown of the active form of the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). This results in increased plasma levels of both intact and biologically active forms of the incretin hormones, thereby primarily improving glycemic control. GLP-1 agonists have been shown to improve glycaemic control, weight loss and in retrospective studies, liver enzymes in patients with type 2 diabetes, making them an attractive treatment option for NASH. Liraglutide, a long-acting GLP-1 analogue, has been verified that can reduce metabolic dysfunction, insulin resistance and lipotoxicity in the key metabolic organs in the pathogenesis of NASH. Thus, GLP-1 agonists may offer the potential for a disease-modifying intervention in NASH.
• Thyroid Hormone Receptor-β Agonist
  Thyroid hormones play an important role in cell development, growth and metabolism, and are essential for the healthy function of almost all tissues. Researches made it possible to improve the design of thyroid receptor β (TRβ1)-selective thyromimetics, and a number of different ligands were subsequently developed, including sobetirome (GC-1), eprotirome (KB2115), MB07811 (VK2809), and-most recently-MGL3196. MGL-3196, a selective thyroid hormone receptor β agonist, significantly decreases hepatic fat in NASH patients in a 36 week serial liver biopsy study.
• mTOR Inhibitors
  The mechanical targets of rapamycin (mTOR) complex 1 (mTORC1) and mTORC2 generally promote anabolic responses by stimulating protein synthesis, glycolysis, mitochondrial functions, and lipid synthesis to influence proliferation and survival, effector and memory responses, innate training and tolerance. Deactivation of mTOR restores cell homeostasis after immune activation and optimizes antigen presentation and memory T-cell generation. The mTOR pathway plays an important role in insulin resistance, type II diabetes, adipogenesis, angiogenesis, and tumor development. Moreover, mTOR inhibitors have been considered as potential NASH treatments.

Fig.2 Metabolic control by mTOR. (Linke, 2017)

If you are interested in the strategies of drug discovery that we provide for the treatment of NASH, please get in touch with us. Creative Biolabs also provides services based on other mechanism. For more details and information, please feel free to contact us for more information.

References

1. Degirolamo, C.; et al. Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23. Nature reviews Drug discovery. 2016, 15(1): 51.
2. Linke, M.;et al. mTORC1 and mTORC2 as regulators of cell metabolism in immunity. FEBS letters. 2017, 591(19): 3089-3103.

For Research Use Only.