title: Endothelin-1 suppresses long-chain fatty acid uptake and glucose uptake via distinct mechanisms in 3T3-L1 adipocytes.
abstract: Endothelin-1 (ET-1) has been demonstrated to induce insulin resistance (IR) and lipolysis, raising the possibility that ET-1 may also contribute to the elevated fatty acid levels in IR-associated comorbidities. We attempted to evaluate whether ET-1 also affects the long-chain fatty acid (LCFA) utilization in 3T3-L1 adipocytes. The effects of chronic ET-1 exposure on basal and insulin-stimulated LCFA uptake, and LCFA uptake kinetics were examined in 3T3-L1 adipocytes. Chronic exposure to ET-1 induced IR and suppressed basal and insulin-stimulated LCFA uptake. Given that insulin acutely stimulates LCFA uptake, there was dramatically similar trend of dose-response curves for ET-1-suppressed LCFA uptake, and also similar corresponding IC₅₀ values, between basal and insulin-stimulated states, reflecting that ET-1 predominantly suppresses basal LCFA uptake. Results of LCFA kinetics, western blots, and CD36 inhibition using sulfosuccinimidyl oleate (SSO) revealed that suppression of LCFA uptake by ET-1 is associated with downregulation of CD36. ET type A receptor (ET(A)R) antagonist BQ-610 reversed the IR induction and the ET-1-suppressed LCFA uptake. Exogenous replenishment of phosphatidylinositol (PI) 4, 5-bisphosphate (PIP₂) prevented IR induction, but not the suppression of LCFA uptake by ET-1. Pharmacological inhibition of the activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) completely blocked the ET-1-suppressed LCFA uptake. Serving as an inducer of IR, ET-1 also chronically suppresses LCFA uptake via PIP₂-independent and ERK-dependent pathway. The interplay between impaired glucose disposal and diminished LCFA utilization, induced by ET-1, could worsen the dysregulation of adipose metabolism and energy homeostasis in insulin-resistant states.
authors.affiliation: Institutes of Physiology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yueh
authors.initials: Y
authors.lastname: Chien
authors.forename: Ying-Hsiu
authors.initials: YH
authors.lastname: Lai
authors.forename: Ching Fai
authors.initials: CF
authors.lastname: Kwok
authors.forename: Low-Tone
authors.initials: LT
authors.lastname: Ho
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D019332:Endothelin-1 / Q000378:metabolism / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects; D005227:Fatty Acids / Q000493:pharmacokinetics*; D005947:Glucose / Q000493:pharmacokinetics*; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D053858:Metabolic Networks and Pathways / Q000502:physiology; D051379:Mice; D044022:Receptor, Endothelin A / Q000378:metabolism / Q000502:physiology; D013997:Time Factors
chemical_list: D019332:Endothelin-1; D005227:Fatty Acids; D007328:Insulin; D044022:Receptor, Endothelin A; D005947:Glucose