Nonalcoholic fatty liver disease (NAFLD) represents a global healthcare challenge; it is the hepatic manifestation of metabolic syndrome and is strongly associated with developing type 2diabetes mellitus (T2DM). Liver fat accumulation is the first step of disease progression that triggers hepatic lipotoxicity. The role of ceramides in inducing deleterious effects on hepatic metabolism is now well-accepted. Yet, the specific role of stress responsive sphingomyelinase activation under lipotoxic conditions remains under-investigated. The complexity of NAFLD pathogenesis contributes to lack of proper investigatory model, limiting progression in developing and testing novel treatment and prevention strategies. Here, we first report a convenient in-vitro human cell-based model with great resemblance to in-vivo NAFLD hallmarks. Neutral Sphingomyelinase (nSMase2) expression and activity was found to be elevated in both the liver of high fat steatosis mouse models and in HepG2-steatosis cell models. Meanwhile, the functional inhibition of nSMase2 prevented hepatotoxicity-induced pathologies by significantly reducing intracellular lipid accumulation and prevented the upregulation of TNF-α triggered inflammation. Furthermore, inhibition of nSMase2 showed significant increase in PPARα at both gene and protein levels, while PPARα reduction was observed under the stimulation of nSMase2 activity by its agonist daunorubicin (DNR). Together the presented data highlight the role of nSMase2 in the pathogenesis of NAFLD and other disorders linked to hepatic steatosis, providing a novel therapeutic target.


F. Alrashed: None. H. Arefanian: None. S.T. Sindhu: None. F. Bahman: None. H. AlSaeed: None. A. Al Madhoun: None. F. Alzaid: None. F. Al-Mulla: None. R. Ahmad: None.


Kuwait Foundation for the Advancement of Sciences (RA0402021)

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