Targeting ASMase in Alcoholic Liver Disease

A recent work by the IDIBAPS team Mitochondrial regulation of cell death and steatohepatitis, led by Dr. José Carlos Fernández-Checa from IIBB-CSIC, provides evidence for acid SMase (ASMase) as a therapeutic target in alcoholic liver disease (ALD). ASMase mediates apoptosis in response to cell death receptors, chemotherapy or ionizing radiation and has emerged as a critical player in liver fibrosis. The work, with Anna Fernandez and Núria Matias as its first authors, was published in Journal of Hepatology and highlighted in Nature Reviews Gastroenterology & Hepatology.

ALD is a major health concern of alcohol abuse and a leading cause of liver-related morbidity and mortality. ALD pathogenesis still remains poorly understood what has greatly limited the availability of efficient therapeutic options. Recent findings have provided evidence that acid sphingomyelinase (ASMase) links alcohol consumption to endoplasmic reticulum (ER) stress, a key mechanism of ALD determining hepatic steatosis and liver injury and thought to be caused by alcohol-mediated increase in homocysteine (Hcy) levels.

ASMase-knockout mice fed an alcohol diet were found resistant to alcohol-induced hepatic steatosis, increased lipogenesis and ER stress, effects that were seen only in wild type mice. Intriguingly, these effects were independent of alcohol-mediated hyperhomocysteinemia. Another key finding was that alcohol-induced ASMase-mediated ER stress triggers the induction of StARD1, a cholesterol-transporting polypeptide that regulates mitochondrial cholesterol trafficking. Consequently, ASMase knockout mice were insensitive to alcohol-induced mitochondrial cholesterol loading and subsequent mitochondrial GSH depletion, which in turn sensitized to circulating and cell-bound TNF susceptibility and liver injury. The findings in ASMase null mice were reproduced in wild type mice after pharmacological ASMase inhibition and increased expression of ASMase, StARD1 and ER stress markers were seen in liver biopsies of patients with acute alcoholic hepatitis.

Overall these findings point that targeting ASMase may be of relevance in human ALD and provide a rationale for further clinical investigation in ALD.

References: Fernandez A, Matias N, Fucho R, Ribas V, Von Montfort C, Nuño N, Baulies A, Martinez L, Tarrats N, Mari M, Colell A, Morales A, Dubuquoy L, Mathurin P, Bataller R, Caballeria J, Elena M, Balsinde J, Kaplowitz N, Garcia-Ruiz C, Fernandez-Checa JC. ASMase is required for chronic alcohol induced hepatic endoplasmic reticulum stress and mitochondrial cholesterol loading. J Hepatol. 2013 Oct;59(4):805-13. doi: 10.1016/j.jhep.2013.05.023. Epub 2013 May 23. Read the abstract

Leake I. Alcoholic liver disease: ASMase implicated in alcoholic liver disease. Nat Rev Gastroenterol Hepatol. 2013 Jul;10(7):384. doi: 10.1038/nrgastro.2013.104. Epub 2013 Jun 11. Read the abstract