Effects of small interfering RNA-mediated hepatic glucagon receptor inhibition on lipid metabolism in db/db mice |
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Authors: | Seongah Han Taro E. Akiyama Stephen F. Previs Kithsiri Herath Thomas P. Roddy Kristian K. Jensen Hong-Ping Guan Beth A. Murphy Lesley A. McNamara Xun Shen Walter Strapps Brian K. Hubbard Shirly Pinto Cai Li Jing Li |
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Affiliation: | *Division of Cardiovascular Disease, Merck Sharp & Dohme Corp., Whitehouse Station, NJ;†Diabetes Research, Merck Sharp & Dohme Corp., Whitehouse Station, NJ;§Pharmacology, and Merck Sharp & Dohme Corp., Whitehouse Station, NJ;**RNA Therapeutics, Merck Sharp & Dohme Corp., Whitehouse Station, NJ |
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Abstract: | Hepatic glucose overproduction is a major characteristic of type 2 diabetes. Because glucagon is a key regulator for glucose homeostasis, antagonizing the glucagon receptor (GCGR) is a possible therapeutic strategy for the treatment of diabetes mellitus. To study the effect of hepatic GCGR inhibition on the regulation of lipid metabolism, we generated siRNA-mediated GCGR knockdown (si-GCGR) in the db/db mouse. The hepatic knockdown of GCGR markedly reduced plasma glucose levels; however, total plasma cholesterol was increased. The detailed lipid analysis showed an increase in the LDL fraction, and no change in VLDL HDL fractions. Further studies showed that the increase in LDL was the result of over-expression of hepatic lipogenic genes and elevated de novo lipid synthesis. Inhibition of hepatic glucagon signaling via siRNA-mediated GCGR knockdown had an effect on both glucose and lipid metabolism in db/db mice. |
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Keywords: | diabetes mellitus glucose dyslipidemia |
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