Inhibition of PRMT3 activity reduces hepatic steatosis without altering atherosclerosis susceptibility in apoE knockout mice

• Published in: Biochimica et biophysica acta. Molecular basis of disease Vol. 1865; no. 6; pp. 1402 - 1409
• Main Authors: Hoekstra, Menno, Nahon, Joya E., de Jong, Laura M., Kröner, Mara J., de Leeuw, Lidewij R., Van Eck, Miranda
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.06.2019
• Subjects: Adipose Tissue, White - drug effects; Adipose Tissue, White - enzymology; Adipose Tissue, White - pathology; Allosteric Regulation - drug effects; Animals; Aorta - drug effects; Aorta - metabolism; Aorta - pathology; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Atherosclerosis; Atherosclerosis - enzymology; Atherosclerosis - etiology; Atherosclerosis - genetics; Atherosclerosis - pathology; Cholesterol - metabolism; Diet, High-Fat - adverse effects; Disease Models, Animal; Disease Susceptibility; Enzyme Inhibitors - pharmacology; Fatty Liver - etiology; Fatty Liver - genetics; Fatty Liver - pathology; Fatty Liver - prevention & control; Fatty liver disease; Foam Cells - drug effects; Foam Cells - metabolism; Foam Cells - pathology; Gene Expression Regulation; Hepatic steatosis; Isoquinolines - pharmacology; Liver - drug effects; Liver - enzymology; Liver - pathology; Liver X Receptors - genetics; Liver X Receptors - metabolism; Male; Mice; Mice, Knockout, ApoE; Mouse model; Pharmacological inhibition; Protein arginine methyltransferase; Protein-Arginine N-Methyltransferases - antagonists & inhibitors; Protein-Arginine N-Methyltransferases - genetics; Protein-Arginine N-Methyltransferases - metabolism; Signal Transduction; Triglycerides - metabolism; cCIMT; TNFα; SDMA; Fatty liver disease; LXR; PRMT3; Protein arginine methyltransferase; UCP1; ADMA; ALT; LPL; Hepatic steatosis; SREBP-1c; ACC1; Pharmacological inhibition; MCP1; Atherosclerosis; oxLDL; FAS; ApoE; Mouse model; SCD1; ABC transporter
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2019.02.012

The nuclear receptor liver X receptor (LXR) impacts on cholesterol metabolism as well as hepatic lipogenesis via transcriptional regulation. It is proposed that inhibition of the protein arginine methyltransferase 3 (PRMT3) uncouples these two transcriptional pathways in vivo by acting as a specific lipogenic coactivator of LXR. Here we validated the hypothesis that treatment with the allosteric PRMT3 inhibitor SGC707 will diminish the hepatic steatosis extent, while leaving global cholesterol metabolism, important in cholesterol-driven pathologies like atherosclerosis, untouched. For this purpose, 12-week old hyperlipidemic apolipoprotein E knockout mice were fed a Western-type diet for six weeks to induce both hepatic steatosis and atherosclerosis. The mice received 3 intraperitoneal injections with SGC707 or solvent control per week. Mice chronically treated with SGC707 developed less severe hepatic steatosis as exemplified by the 51% reduced (P < 0.05) liver triglyceride levels. In contrast, the extent of in vivo macrophage foam cell formation and aortic root atherosclerosis was not affected by SGC707 treatment. Interestingly, SGC707-treated mice gained 94% less body weight (P < 0.05), which was paralleled by changes in white adipose tissue morphology, i.e. reduction in adipocyte size and browning. In conclusion, we have shown that through PRMT3 inhibitor treatment specific functions of LXR involved in respectively the development of fatty liver disease and atherosclerosis can be uncoupled, resulting in an overall diminished hepatic steatosis extent without a negative impact on atherosclerosis susceptibility. As such, our studies highlight that PRMT3 inhibition may constitute a novel therapeutic approach to limit the development of fatty liver disease in humans. •Chronic SGC707 treatment inhibits the development of hepatic steatosis•Hypercholesterolemia extent and immune status are similar after SGC707 treatment•PRMT3 inhibition does not negatively impact on atherosclerosis susceptibility