Rescue of Mtp siRNA-induced hepatic steatosis by DGAT2 siRNA silencing

Microsomal triglyceride transfer protein (Mtp) inhibitors represent a novel therapeutic approach to lower circulating LDL cholesterol, although therapeutic development has been hindered by the observed increase in hepatic triglycerides and liver steatosis following treatment. Here, we used small int...

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Bibliographic Details
Published in:Journal of lipid research 2012-05, Vol.53 (5), p.859-867
Main Authors: Tep, Samnang, Mihaila, Radu, Freeman, Alexander, Pickering, Victoria, Huynh, Felicia, Tadin-Strapps, Marija, Stracks, Allison, Hubbard, Brian, Caldwell, Jeremy, Flanagan, W. Michael, Kuklin, Nelly A., Ason, Brandon
Format: Article
Language:English
Subjects:
Animals
Apolipoproteins B - deficiency
Apolipoproteins B - genetics
atherosclerosis
Carrier Proteins - genetics
Carrier Proteins - metabolism
Cholesterol - blood
combination therapies
Diacylglycerol O-Acyltransferase - deficiency
Diacylglycerol O-Acyltransferase - genetics
dyslipidemia
Fatty Liver - blood
Fatty Liver - enzymology
Fatty Liver - genetics
Fatty Liver - metabolism
Gene Silencing
Liver - metabolism
low density lipoprotein cholesterol
Male
Mice
RNA, Small Interfering - genetics
RNAi
Triglycerides - metabolism
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Summary:Microsomal triglyceride transfer protein (Mtp) inhibitors represent a novel therapeutic approach to lower circulating LDL cholesterol, although therapeutic development has been hindered by the observed increase in hepatic triglycerides and liver steatosis following treatment. Here, we used small interfering RNAs (siRNA) targeting Mtp to achieve target-specific silencing to study this phenomenon and to determine to what extent liver steatosis is induced by changes in Mtp expression. We observed that Mtp silencing led to a decrease in many genes involved in hepatic triglyceride synthesis. Given the role of diacylglycerol O-acyltransferase 2 (Dgat2) in regulating hepatic triglyceride synthesis, we then evaluated whether target-specific silencing of both Dgat2 and Mtp were sufficient to attenuate Mtp silencing-induced liver steatosis. We showed that the simultaneous inhibition of Dgat2 and Mtp led to a decrease in plasma cholesterol and a reduction in the accumulation of hepatic triglycerides caused by the inhibition of Mtp. Collectively, these findings provide a proof-of-principle for a triglyceride synthesis/Mtp inhibitor combination and represent a potentially novel approach for therapeutic development in which targeting multiple pathways can achieve the desired response.
ISSN:0022-2275
1539-7262
DOI:10.1194/jlr.M021063