title: Fenofibrate insulates diacylglycerol in lipid droplet/ER and preserves insulin signaling transduction in the liver of high fat fed mice.
abstract: Hepatic steatosis is often associated with insulin resistance as a hallmark of the metabolic syndrome in the liver. The present study investigated the effects of PPARα activation induced by fenofibrate (FB) on the relationship of insulin resistance and hepatic steatosis in mice fed a high-fat (HF) diet, which increases lipid influx into the liver. Mice were fed HF diet to induce insulin resistance and hepatic steatosis with or without FB. FB activated PPARα and ameliorated HF diet-induced glucose intolerance and hepatic insulin resistance without altering either hepatic steatosis or inflammation signaling (JNK or IKK). Interestingly, FB treatment simultaneously increased fatty acid (FA) synthesis (50%) and oxidation (66%, both p<0.01) into intermediate lipid metabolites, suggesting a FA oxidation-synthesis cycling in operation. Associated with these effects, diacylglycerols (DAGs) were sequestered within the lipid droplet/ER compartment, thus reducing their deposition in the cellular membrane, which is known to impair insulin signal transduction. These findings suggest that the reduction in membrane DAGs (rather than total hepatic steatosis) may be critical for the protection by fenofibrate-induced PPARα activation against hepatic insulin resistance induced by dietary fat.
authors.affiliation: Lipid Biology and Metabolic Disease Laboratory, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia.
authors.forename: Stanley M H
authors.initials: SM
authors.lastname: Chan
authors.affiliation: Lipid Biology and Metabolic Disease Laboratory, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia.
authors.forename: Xiao-Yi
authors.initials: XY
authors.lastname: Zeng
authors.affiliation: Lipid Biology and Metabolic Disease Laboratory, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia.
authors.forename: Ruo-Qiong
authors.initials: RQ
authors.lastname: Sun
authors.affiliation: Lipid Biology and Metabolic Disease Laboratory, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia.
authors.forename: Eunjung
authors.initials: E
authors.lastname: Jo
authors.affiliation: Lipid Biology and Metabolic Disease Laboratory, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia.
authors.forename: Xiu
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Lipid Biology and Metabolic Disease Laboratory, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Lipid Biology and Metabolic Disease Laboratory, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia.
authors.forename: Songpei
authors.initials: S
authors.lastname: Li
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong, China.
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
authors.affiliation: Department of Physiology, Monash University, Melbourne, VIC, Australia.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Watt
authors.affiliation: Lipid Biology and Metabolic Disease Laboratory, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia. Electronic address: jiming.ye@rmit.edu.au.
authors.forename: Ji-Ming
authors.initials: JM
authors.lastname: Ye
mesh_terms: D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D004075:Diglycerides / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism*; D011345:Fenofibrate / Q000494:pharmacology*; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D066292:Lipid Droplets / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047493:PPAR alpha / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D004075:Diglycerides; D000960:Hypolipidemic Agents; D007328:Insulin; D047493:PPAR alpha; D011345:Fenofibrate
keywords: DAG repartitioning; FA oxidation; FA synthesis; Insulin signaling; PPARα