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• F a, M N, F r, r v, v M C, N N .. ASMase is requi-
Most relevant erNáNDezatiasuChoiBasoNoNtFortuñoet aL
red for chronic alcohol induced hepatic endoplasmic reticulum stress and mitochon-
scientific drial cholesterol loading.J Hepatol. 2013 Oct;59(4):805-13.

articles
• BarBero-CaMps e, FerNáNDez a, MartíNez L, FerNáNDez-CheCa JC, CoLeLL a. APP/PS1 mice
overexpressing SREBP-2 exhibit combined Aβ accumulation and tau pathology un-

derlying Alzheimer’s disease.Hum Mol Genet. 2013 Sep 1;22(17):3460-76.

• garCía-ruiz C, FerNáNDez-CheCa JC. To binge or not to binge: binge drinking disrupts
glucose homeostasis by impairing hypothalamic but not liver insulin signaling.Hepa-

tology. 2013 Jun;57(6):2535-8.

• Marí M, MoraLes a, CoLeLL a, garCía-ruiz C, KapLoWitz N, FerNáNDez-CheCa JC. Mitochon-
drial glutathione: features, regulation and role in disease.Biochim Biophys Acta.

2013 May;1830(5):3317-28.

• garCía-ruiz C, BauLies a, Mari M, garCía-rovés pM, FerNáNDez-CheCa JC. Mitochondrial
dysfunction in non-alcoholic fatty liver disease and insulin resistance: cause or

consequence?Free Radic Res. 2013 Nov;47(11):854-68.

Our recent work, ASMase is required for chronic alcohol induced hepatic endoplasmic
Highlights
reticulum stress and mitochondrial cholesterol loading (J Hepatol. 2013), highlighted in
Nature Reviews Gastroenterology&Hepatology, provides evidence for ASMase as a the-

rapeutic target in alcoholic liver disease (ALD). 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 the-

rapeutic options. Our data 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, independently of alcohol-mediated hyper-

homocysteinemia. Another key finding was that alcohol-induced ASMase-mediated ER
stress triggers the induction of StARD1, a cholesterol-transporting polypeptide that regu-

lates mitochondrial cholesterol trafficking. Consequently, ASMase knockout mice or wild

type mice after pharmacological ASMase inhibition 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. Moreover,
increased expression of ASMase, StARD1 and ER stress markers were seen in liver biop-

sies of patients with acute alcoholic hepatitis, providing a rationale to ASMase targeting

as applicable in human ALD treatment.

A mechanistically related study, APP/PS1 mice overexpressing SREBP-2 exhibit combined
Aß accumulation and tau pathology underlying Alzheimer’s disease (Hum Mol Genet,

2013), highlights the role of cholesterol in the development of Alzheimer’s disease. Our

data shows that that increasing cholesterol accelerates and worsens different pathologi-
cal manifestations of the disease and cognitive deficits. Moreover, the increase of total
13
cholesterol is associated with decreased mitochondrial glutathione (GSH) fraction, and 20
in vivo administration of GSH ester significantly reduced neural degeneration. These re- T
OR
sults, in line with our previous results in liver, demonstrate the importance of preserving P
RE
mitochondrial antioxidant defense as a therapeutic strategy in Alzheimer’s disease.
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