ASMase is required for chronic alcohol induced hepatic endoplasmic reticulum stress and mitochondrial cholesterol loading

Abstract

Background & aims The pathogenesis of alcohol-induced liver disease (ALD) is poorly understood. Here, we examined the role of acid sphingomyelinase (ASMase) in alcohol induced hepatic endoplasmic reticulum (ER) stress, a key mechanism of ALD Methods We examined ER stress, lipogenesis, hyperhomocysteinemia, mitochondrial cholesterol (mChol) trafficking and susceptibility to LPS and concanavalin-A in ASMase−/− mice fed alcohol. Results Alcohol feeding increased SREBP-1c, DGAT-2 and FAS mRNA in ASMase+/+ but not in ASMase−/− mice. Compared to ASMase+/+ mice, ASMase−/− mice exhibited decreased expression of ER stress markers induced by alcohol, but the level of tunicamycin-mediated upregulation of ER stress markers and steatosis was similar in both types of mice. The increase in homocysteine levels induced by alcohol feeding was comparable in both ASMase+/+ mice and ASMase−/− mice. Exogenous ASMase, but not neutral SMase, induced ER stress by perturbing ER Ca2+ homeostasis. Moreover, alcohol-induced mChol loading and StARD1 overexpression were blunted in ASMase−/− mice. Tunicamycin upregulated StARD1 expression and this outcome was abrogated by tauroursodeoxycholic acid. Alcohol-induced liver injury and sensitization to LPS and concanavalin-A were prevented in ASMase−/− mice. These effects were reproduced in alcohol-fed TNFR1/R2−/− mice. Moreover, ASMase does not impair hepatic regeneration following partial hepatectomy. Of relevance, liver samples from patients with alcoholic hepatitis exhibited increased expression of ASMase, StARD1 and ER stress markers. Conclusion Our data indicate that ASMase is critical for alcohol-induced ER stress, and provide a rationale for further clinical investigation in ALD.

Mitochondrial DNA–enriched microparticles promote acute-on-chronic alcoholic neutrophilia and hepatotoxicity

“…The schematic diagram illustrating the proposed mechanism is summarized in Figure 9. The role of ER stress in the pathogenesis of alcohol-induced liver injury has been described, especially in a mouse model of chronic ethanol feeding (27)(28)(29). In our present study, we found that the activation of ER stress is much greater in the E10d + 1B ethanol model when compared with either chronic ethanol feeding (E10d) or binge (1B) model alone in mice.…”

“…ER stress is known to induce liver injury via the induction of apoptosis (27)(28)(29). In the current study, we provided several lines of evidence suggesting a novel mechanism by which ER stress promotes liver injury via the induction of circulating neutrophils and hepatic neutrophil infiltration.…”

“…Because it has been reported that chronic ethanol feeding induces hepatic ER stress (27)(28)(29), and ER stress promotes hepatocytes to release EVs (30), we asked whether elevation of serum MPs after E10d + 1B ethanol feeding was also due to the induction of hepatic ER stress.…”

Lipotoxic lethal and sublethal stress signaling in hepatocytes: relevance to NASH pathogenesis

“…Ceramide can also be generated by hydrolysis of sphingolipids by sphingomyelinases in the plasma membrane or lysosomes, via salvage pathways, without direct synthesis from palmitate (23). Though sphingomyelinases have been studied in alcohol-induced liver disease (86), their contribution to obesity-associated NASH is an area that warrants additional studies. Two recent studies have underscored the importance of C16:0 ceramide in the pathogenesis of dietary steatohepatitis in mice and suggested a role for this in humans.…”

Acid Sphingomyelinase Promotes Endothelial Stress Response in Systemic Inflammation and Sepsis

“…In this context, the endothelium undergoes structural and functional alterations which may result in remote organ failure that is central to the pathophysiological derangements of multiple organ dysfunction syndrome (5,42). Despite numerous reports describing an increased activity of SMPD1 in several clinical conditions (43,44), there is a lack of information regarding the action of SMPD1 in particular on endothelial cells mediated by a plethora of proinflammatory serum constituents. Therefore, we used a human in vitro setting (HMEC-1) to study various pathophysiological processes as these cells display most of the morphological and functional characteristics of endothelial cellular damage control ( Figure 5D) including autocrine signaling.…”