miR-33 inhibition attenuates the effect of liver X receptor agonist T0901317 on expression of liver X receptor alpha in mice liver

Abbas Mohammadi, Hossein Fallah, Beydolah Shahouzehi, Hamid Najafipour

Abstract


BACKGROUND: microRNAs play pivotal roles in metabolism and other aspects of cell biology. microRNA-33 and liver X receptor (LXR) affect lipid metabolism and cholesterol trafficking. In this study, we evaluated effects of co-administration of miR-33 inhibitor and LXR activator on LXR-α and adenosine triphosphate-binding cassette transporter A1 (ABCA1) expression in mice liver.

METHODS: Twenty-four mice were randomly allocated into four groups (n = 6). Group 1 mice received standard chow diet without any treatment, group 2 received 30 mg/kg/48 hour LXR agonist (T0901317), group 3 received 1 mg/kg/48 hour in vivo locked nucleic acids (LNA) anti-miR-33 and group 4 received both T0901317 and in vivo LNA anti-miR-33. All treatments were administrated through intraperitoneal injection (IP). After 7 days and at the end of the study, mice were sacrificed, liver tissues were excised and blood samples were collected. LXR-α and ABCA1 genes and protein expression were quantified by real-time polymerase chain reaction (PCR) and western blotting, respectively.

RESULTS: LXR activation caused LXR-α and ABCA1 mRNA (P < 0.050) and protein elevation as compared to control (P < 0.001). miR-33 inhibition attenuates T0901317 effect on LXR-α expression in group IV. Co-administration of T0901317 and anti-miR-33 remarkably elevated high-density lipoprotein cholesterol (HDL-C) levels, compared to control group (P = 0.001). Separate administration of T0901317 and anti-miR-33 also elevated HDL-C levels (P < 0.010).

CONCLUSION: Co-administration of T0901317 and anti-miR-33 can be considered as a good therapeutic alternative for atherosclerosis because miR-33 inhibition reduced lipogenic effects of LXR-α activator and also helps LXR-α agonist to increase reverse cholesterol transport (RCT) and also HDL-C as antiatherogenic effects.

 

 


Keywords


Atherosclerosis; mir-33 Human; T0901317; Liver X Receptor-Alpha; ABCA1 Protein

References


Najafi-Shoushtari SH. MicroRNAs in cardiometabolic disease. Curr Atheroscler Rep 2011; 13(3): 202-7.

Ramirez CM, Rotllan N, Vlassov AV, Davalos A, Li M, Goedeke L, et al. Control of cholesterol metabolism and plasma high-density lipoprotein levels by microRNA-144. Circ Res 2013; 112(12): 1592-601.

Soumian S, Albrecht C, Davies AH, Gibbs RG. ABCA1 and atherosclerosis. Vasc Med 2005; 10(2): 109-19.

Annema W, Dikkers A, de Boer JF, Gautier T, Rensen PC, Rader DJ, et al. ApoE promotes hepatic selective uptake but not RCT due to increased ABCA1-mediated cholesterol efflux to plasma. J Lipid Res 2012; 53(5): 929-40.

Horie T, Baba O, Kuwabara Y, Chujo Y, Watanabe S, Kinoshita M, et al. MicroRNA-33 deficiency reduces the progression of atherosclerotic plaque in ApoE-/- mice. J Am Heart Assoc 2012; 1(6): e003376.

Rottiers V, Naar AM. MicroRNAs in metabolism and metabolic disorders. Nat Rev Mol Cell Biol 2012; 13(4): 239-50.

Yamamoto S, Tanigawa H, Li X, Komaru Y, Billheimer JT, Rader DJ. Pharmacologic suppression of hepatic ATP-binding cassette transporter 1 activity in mice reduces high-density lipoprotein cholesterol levels but promotes reverse cholesterol transport. Circulation 2011; 124(12): 1382-90.

Basso F, Freeman L, Knapper CL, Remaley A, Stonik J, Neufeld EB, et al. Role of the hepatic ABCA1 transporter in modulating intrahepatic cholesterol and plasma HDL cholesterol concentrations. J Lipid Res 2003; 44(2): 296-302.

Calkin AC, Tontonoz P. Liver x receptor signaling pathways and atherosclerosis. Arterioscler Thromb Vasc Biol 2010; 30(8): 1513-8.

Zhao C, Dahlman-Wright K. Liver X receptor in cholesterol metabolism. J Endocrinol 2010; 204(3): 233-40.

Kappus MS, Murphy AJ, Abramowicz S, Ntonga V, Welch CL, Tall AR, et al. Activation of liver X receptor decreases atherosclerosis in Ldlr(-)/(-) mice in the absence of ATP-binding cassette transporters A1 and G1 in myeloid cells. Arterioscler Thromb Vasc Biol 2014; 34(2): 279-84.

Chisholm JW, Hong J, Mills SA, Lawn RM. The LXR ligand T0901317 induces severe lipogenesis in the db/db diabetic mouse. J Lipid Res 2003; 44(11): 2039-48.

Baranowski M. Biological role of liver X receptors. J Physiol Pharmacol 2008; 59(Suppl 7): 31-55.

Ma Z, Deng C, Hu W, Zhou J, Fan C, Di S, et al. Liver X Receptors and their Agonists: Targeting for Cholesterol Homeostasis and Cardiovascular Diseases. Curr Issues Mol Biol 2017; 22: 41-64.

Terasaka N, Hiroshima A, Koieyama T, Ubukata N, Morikawa Y, Nakai D, et al. T-0901317, a synthetic liver X receptor ligand, inhibits development of atherosclerosis in LDL receptor-deficient mice. FEBS Lett 2003; 536(1-3): 6-11.

Li M, Meng X, Xu J, Huang X, Li H, Li G, et al. GPR40 agonist ameliorates liver X receptor-induced lipid accumulation in liver by activating AMPK pathway. Sci Rep 2016; 6: 25237.

Yap F, Craddock L, Yang J. Mechanism of AMPK suppression of LXR-dependent Srebp-1c transcription. Int J Biol Sci 2011; 7(5): 645-50.

Lee J, Hong SW, Park SE, Rhee EJ, Park CY, Oh KW, et al. AMP-activated protein kinase suppresses the expression of LXR/SREBP-1 signaling-induced ANGPTL8 in HepG2 cells. Mol Cell Endocrinol 2015; 414: 148-55.

He F, Han C, Liu D, Wan H, Wang J, Liu H, et al. Effect of a synthetic liver X receptor agonist TO901317 on cholesterol concentration in goose primary hepatocytes. Ital J Anim Sci 2014; 13(1): 2979.

Kostopoulou F, Malizos KN, Papathanasiou I, Tsezou A. MicroRNA-33a regulates cholesterol synthesis and cholesterol efflux-related genes in osteoarthritic chondrocytes. Arthritis Res Ther 2015; 17: 42.

Najafipour H, Vakili A, Shahouzehi B, Soltani HA, Masoomi Y, Yeganeh Hajahmadi M, et al. Investigation of changes in apelin receptor mRNA and protein expression in the myocardium and aorta of rats with two-kidney, one-clip (2K1C) Goldblatt hypertension. J Physiol Biochem 2015; 71(2): 165-75.

Zheng F, Zhang S, Lu W, Wu F, Yin X, Yu D, et al. Regulation of insulin resistance and adiponectin signaling in adipose tissue by liver X receptor activation highlights a cross-talk with PPARgamma. PLoS One 2014; 9(6): e101269.

Fulco M, Sartorelli V. Comparing and contrasting the roles of AMPK and SIRT1 in metabolic tissues. Cell Cycle 2008; 7(23): 3669-79.

Rohrl C, Eigner K, Winter K, Korbelius M, Obrowsky S, Kratky D, et al. Endoplasmic reticulum stress impairs cholesterol efflux and synthesis in hepatic cells. J Lipid Res 2014; 55(1): 94-103.

Bommer GT, MacDougald OA. Regulation of lipid homeostasis by the bifunctional SREBF2-miR33a locus. Cell Metab 2011; 13(3): 241-7.

Gerin I, Clerbaux LA, Haumont O, Lanthier N, Das AK, Burant CF, et al. Expression of miR-33 from an SREBP2 intron inhibits cholesterol export and fatty acid oxidation. J Biol Chem 2010; 285(44): 33652-61.

Gharipour M, Sadeghi M. Pivotal role of microRNA-33 in metabolic syndrome: A systematic review. ARYA Atheroscler 2013; 9(6): 372-6.

Rayner KJ, Suarez Y, Davalos A, Parathath S, Fitzgerald ML, Tamehiro N, et al. MiR-33 contributes to the regulation of cholesterol homeostasis. Science 2010; 328(5985): 1570-3.

Li Y, Xu S, Mihaylova MM, Zheng B, Hou X, Jiang B, et al. AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab 2011; 13(4): 376-88.


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