title: Rescue of Mtp siRNA-induced hepatic steatosis by DGAT2 siRNA silencing.
abstract: 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.
authors.affiliation: Sirna Therapeutics/Merck & Co. Inc., San Francisco, CA 94158; and. Electronic address: samnang.tep@gmail.com.
authors.forename: Samnang
authors.initials: S
authors.lastname: Tep
authors.affiliation: Sirna Therapeutics/Merck & Co. Inc., San Francisco, CA 94158; and.
authors.forename: Radu
authors.initials: R
authors.lastname: Mihaila
authors.affiliation: Sirna Therapeutics/Merck & Co. Inc., San Francisco, CA 94158; and.
authors.forename: Alexander
authors.initials: A
authors.lastname: Freeman
authors.affiliation: Sirna Therapeutics/Merck & Co. Inc., San Francisco, CA 94158; and.
authors.forename: Victoria
authors.initials: V
authors.lastname: Pickering
authors.affiliation: Sirna Therapeutics/Merck & Co. Inc., San Francisco, CA 94158; and.
authors.forename: Felicia
authors.initials: F
authors.lastname: Huynh
authors.affiliation: Sirna Therapeutics/Merck & Co. Inc., San Francisco, CA 94158; and.
authors.forename: Marija
authors.initials: M
authors.lastname: Tadin-Strapps
authors.affiliation: Division of Cardiovascular Diseases-Atherosclerosis, Merck Research Laboratories, Rahway, NJ 07065.
authors.forename: Allison
authors.initials: A
authors.lastname: Stracks
authors.affiliation: Division of Cardiovascular Diseases-Atherosclerosis, Merck Research Laboratories, Rahway, NJ 07065.
authors.forename: Brian
authors.initials: B
authors.lastname: Hubbard
authors.affiliation: Sirna Therapeutics/Merck & Co. Inc., San Francisco, CA 94158; and.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Caldwell
authors.affiliation: Sirna Therapeutics/Merck & Co. Inc., San Francisco, CA 94158; and.
authors.forename: W Michael
authors.initials: WM
authors.lastname: Flanagan
authors.affiliation: Sirna Therapeutics/Merck & Co. Inc., San Francisco, CA 94158; and.
authors.forename: Nelly A
authors.initials: NA
authors.lastname: Kuklin
authors.affiliation: Sirna Therapeutics/Merck & Co. Inc., San Francisco, CA 94158; and. Electronic address: bason@amgen.com.
authors.forename: Brandon
authors.initials: B
authors.lastname: Ason
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000172:deficiency / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood; D051048:Diacylglycerol O-Acyltransferase / Q000172:deficiency* / Q000235:genetics*; D005234:Fatty Liver / Q000097:blood / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D020868:Gene Silencing; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D034741:RNA, Small Interfering / Q000235:genetics*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D001055:Apolipoproteins B; D002352:Carrier Proteins; D034741:RNA, Small Interfering; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein; D002784:Cholesterol; C516957:DGAT2 protein, mouse; D051048:Diacylglycerol O-Acyltransferase