NASH Target Development Service for Acid Sphingomyelinase (ASMase) Inhibitors

Acid sphingomyelinase is a key factor in the pathways of ceramide production, which indirectly contributes to NASH development. Creative Biolabs provides a diverse portfolio of acid sphingomyelinase (ASMase) inhibitor development services for the NASH treatment with high-quality and abundant experience.

What is Acid Sphingomyelinase?

Acid sphingomyelinase, together with neutral sphingomyelinase and alkaline sphingomyelinase, form sphingomyelinase family (SMase), which is a kind of hydrolase enzyme involved in sphingolipid metabolism reactions. Acid sphingomyelinase (ASMase) is a critical metabolism enzyme catalyzing the breakdown of sphingomyelin into ceramide and phosphorylcholine by cleaving the phosphorylcholine linkage. The ASMase activity functions at optimum catalytic reaction conditions pH 4.5~5.0 and temperature of 37ºC, which also may be influenced by cations, pH, lipids, redox and other proteins in the environment. Human ASMase is encoded by the sphingomyelin phosphodiesterase 1 (SMPD1) gene with lysosomal ASMase and two types of secreted ASMase, all of which are implicated in ceramide metabolism. ASMase can be activated by both receptors and non-receptor stimuli, such as death receptors, microorganisms, cytokines, radiation, oxidative stress. In recent years, ASMase has been demonstrated to play an important role in cellular signaling and bioactive processes, especially when it comes to sphingolipid metabolism. ASMase deficiency or SMPD1 gene mutation results in lysosomal storage disorders Niemann-Pick diseases, atherosclerosis, diabetes, etc.

Fig.1 The role of acid sphingomyelinase in sphingolipid metabolism. (Jenkins, 2009)

Acid Sphingomyelinase (ASMase) Inhibitors for NASH Treatment

As mentioned before, intracellular ceramides accumulation is closely associated with the development of non-alcoholic steatohepatitis (NASH). Recently clinical and laboratory studies have revealed that ASMase activation or overexpression may be the key factor of NASH pathogenesis since the biochemical processes of ASMase are mostly related to ceramide production. The pathological mechanism of NASH induced by ASMase may involve in the following factors:

ER stress: ASMase leads to the disruption of Ca²⁺ homeostasis in the endoplasmic reticulum (ER) and thereby induces ER stress, which is the main pathway to regulate insulin resistance, lipogenesis, steatosis, and apoptosis.

Autophagy: ASMase could decrease or disrupt autophagy, which is a newly revealed pathway for lipid degradation and engaged to prevent steatosis.

Lysosomal membrane permeabilization: ASMase increases permeabilization of lysosomal membrane permeabilization, and subsequently causes lysosomal cholesterol accumulation and lipotoxicity.

Other pathogenic factors: metabolism of methionine and phosphatidylcholine alteration, AKT signaling mediated insulin resistance, etc.

As these extensively pathogenic processes of ASMase lead to NASH progression, ASMase now has been suggested to be a critical target in terms of fatty liver disease treatment, particularly NASH therapy. Functional inhibitors of acid sphingomyelinase (FIASMase) are a group of pharmacological molecules suppressing ASMase activity by detaching ASMase from the lysosomal membrane and inducing ASMase degradation. FIASMase and other ASMase inhibitors are promising therapeutic strategies for NASH treatment.

Fig.2 ASMase in steatohepatitis: One target, multiple pathways. (Garcia-Ruiz, 2015)

Acidic sphingomyelinase inhibitors treat NASH by targeting ASMase and inhibiting ASMase to reduce ceramide production and accumulation in the liver. After years of efforts, Creative Biolabs now can offer comprehensive acidic sphingomyelinase inhibitors services to global clients. Other NASH treatment services also include but not limited to Biomarkers for NASH Diagnosis, Target Discovery and Therapeutic Strategies, Preclinical Models of NASH, and customized services. Please feel free to contact us or directly sent us an inquiry.

References

1. Jenkins, R.W.; et al. Roles and Regulation of Secretory and Lysosomal Acid Sphingomyelinase. Cell Signal. 2009, 21(6): 836-846.
2. Garcia-Ruiz, C.; et al. Acid sphingomyelinase-ceramide system in steatohepatitis: A novel target regulating multiple pathways. Journal of Hepatology. 2015, 62(1): 219-233.