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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2012-05-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520392166 |
| _version_ | 1818735022303084544 |
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| author | Samnang Tep Radu Mihaila Alexander Freeman Victoria Pickering Felicia Huynh Marija Tadin-Strapps Allison Stracks Brian Hubbard Jeremy Caldwell W. Michael Flanagan Nelly A. Kuklin Brandon Ason |
| author_facet | Samnang Tep Radu Mihaila Alexander Freeman Victoria Pickering Felicia Huynh Marija Tadin-Strapps Allison Stracks Brian Hubbard Jeremy Caldwell W. Michael Flanagan Nelly A. Kuklin Brandon Ason |
| author_sort | Samnang Tep |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-18T00:14:39Z |
| format | Article |
| id | doaj.art-fdcfd415604344018fb272350374bf38 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-18T00:14:39Z |
| publishDate | 2012-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-fdcfd415604344018fb272350374bf382022-12-21T21:27:33ZengElsevierJournal of Lipid Research0022-22752012-05-01535859867Rescue of Mtp siRNA-induced hepatic steatosis by DGAT2 siRNA silencingSamnang Tep0Radu Mihaila1Alexander Freeman2Victoria Pickering3Felicia Huynh4Marija Tadin-Strapps5Allison Stracks6Brian Hubbard7Jeremy Caldwell8W. Michael Flanagan9Nelly A. Kuklin10Brandon Ason11To whom correspondence should be addressed.; Sirna Therapeutics/Merck & Co. Inc., San Francisco, CA 94158; andSirna Therapeutics/Merck & Co. Inc., San Francisco, CA 94158; andSirna Therapeutics/Merck & Co. Inc., San Francisco, CA 94158; andSirna Therapeutics/Merck & Co. Inc., San Francisco, CA 94158; andSirna Therapeutics/Merck & Co. Inc., San Francisco, CA 94158; andSirna Therapeutics/Merck & Co. Inc., San Francisco, CA 94158; andDivision of Cardiovascular Diseases–Atherosclerosis, Merck Research Laboratories, Rahway, NJ 07065Division of Cardiovascular Diseases–Atherosclerosis, Merck Research Laboratories, Rahway, NJ 07065Sirna Therapeutics/Merck & Co. Inc., San Francisco, CA 94158; andSirna Therapeutics/Merck & Co. Inc., San Francisco, CA 94158; andSirna Therapeutics/Merck & Co. Inc., San Francisco, CA 94158; andTo whom correspondence should be addressed.; Sirna Therapeutics/Merck & Co. Inc., San Francisco, CA 94158; and; To whom correspondence should be addressed.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.http://www.sciencedirect.com/science/article/pii/S0022227520392166RNAicombination therapieslow density lipoprotein cholesteroldyslipidemiaatherosclerosis |
| spellingShingle | Samnang Tep Radu Mihaila Alexander Freeman Victoria Pickering Felicia Huynh Marija Tadin-Strapps Allison Stracks Brian Hubbard Jeremy Caldwell W. Michael Flanagan Nelly A. Kuklin Brandon Ason Rescue of Mtp siRNA-induced hepatic steatosis by DGAT2 siRNA silencing Journal of Lipid Research RNAi combination therapies low density lipoprotein cholesterol dyslipidemia atherosclerosis |
| title | Rescue of Mtp siRNA-induced hepatic steatosis by DGAT2 siRNA silencing |
| title_full | Rescue of Mtp siRNA-induced hepatic steatosis by DGAT2 siRNA silencing |
| title_fullStr | Rescue of Mtp siRNA-induced hepatic steatosis by DGAT2 siRNA silencing |
| title_full_unstemmed | Rescue of Mtp siRNA-induced hepatic steatosis by DGAT2 siRNA silencing |
| title_short | Rescue of Mtp siRNA-induced hepatic steatosis by DGAT2 siRNA silencing |
| title_sort | rescue of mtp sirna induced hepatic steatosis by dgat2 sirna silencing |
| topic | RNAi combination therapies low density lipoprotein cholesterol dyslipidemia atherosclerosis |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520392166 |
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