title: 4-Hydroxyisoleucine ameliorates fatty acid-induced insulin resistance and inflammatory response in skeletal muscle cells.
abstract: The 4-hydroxyisoleucine (4-HIL), an unusual amino acid isolated from the seeds of Trigonella foenum-graecum was investigated for its metabolic effects to ameliorate free fatty acid-induced insulin resistance in skeletal muscle cells. An incubation of L6 myotubes with palmitate inhibited insulin stimulated-glucose uptake and -translocation of glucose transporter 4 (GLUT4) to the cell surface. Addition of 4-HIL strongly prevented this inhibition. We then examined the insulin signaling pathway, where 4-HIL effectively inhibited the ability of palmitate to reduce insulin-stimulated phosphorylation of insulin receptor substrate-1 (IRS-1), protein kinase B (PKB/AKT), AKT substrate of 160 kD (AS160) and glycogen synthase kinase 3β (GSK-3β) in L6 myotubes. Moreover, 4-HIL presented strong inhibition on palmitate-induced production of reactive oxygen species (ROS) and associated inflammation, as the activation of NF-κB, JNK1/2, ERK1/2 and p38 MAPK was greatly reduced. 4-HIL also inhibited inflammation-stimulated IRS-1 serine phosphorylation and restored insulin-stimulated IRS-1 tyrosine phosphorylation in the presence of palmitate, leading to enhanced insulin sensitivity. These findings suggested that 4-HIL could inhibit palmitate-induced, ROS-associated inflammation and restored insulin sensitivity through regulating IRS-1 function.
authors.affiliation: Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Chandan Kumar
authors.initials: CK
authors.lastname: Maurya
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Rohit
authors.initials: R
authors.lastname: Singh
authors.affiliation: Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Natasha
authors.initials: N
authors.lastname: Jaiswal
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: K
authors.initials: K
authors.lastname: Venkateswarlu
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India. Electronic address: t_narendra@cdri.res.in.
authors.forename: Tadigoppula
authors.initials: T
authors.lastname: Narender
authors.affiliation: Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India. Electronic address: akhilesh_tamrakar@cdri.res.in.
authors.forename: Akhilesh Kumar
authors.initials: AK
authors.lastname: Tamrakar
mesh_terms: D000818:Animals; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance; D007532:Isoleucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C104672:4-hydroxyisoleucine; D005227:Fatty Acids; D020690:GTPase-Activating Proteins; D051275:Glucose Transporter Type 4; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D017382:Reactive Oxygen Species; C495694:Slc2a4 protein, rat; C533101:TBC1D4 protein, rat; D007532:Isoleucine; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: 4-Hydroxyisoleucine; Diabetes; Glucose uptake; Inflammation; Insulin resistance