title: Thioredoxin interacting protein mediates lipid-induced impairment of glucose uptake in skeletal muscle.
abstract: Insulin resistance (IR) is an important determinant of type-2 diabetes mellitus (T2DM). Free fatty acids (FFAs) induce IR by various mechanisms. A surfeit of circulating FFA leads to intra-myocellular lipid accumulation that induces mitochondrial ROS generation and worsens IR. However, the molecular mechanisms behind are unclear. We identified thioredoxin interacting protein (TxNIP), which is overexpressed in T2DM, to be a promoter of ROS-induced IR. We observed upregulation of TxNIP upon palmitate treatment in skeletal muscle cells that led to ROS generation and Glut-4 downregulation resulting in impaired glucose-uptake. FFA-induced overexpression of TxNIP gene was mediated through the activation of its bona-fide trans activator, ChREBP. Further, Palmitate-induced impairment in AMPK-SIRT-1 pathway resulted in overexpression of ChREBP. While Fenofibrate, abrogated PA-induced TxNIP expression and ROS generation in skeletal muscle cells, Saroglitazar, a dual PPARα/γ-agonist, not only inhibited PA-induced TXNIP expression but also led to greater improvement in glucose uptake. Taken together, TxNIP appears to be an important factor in FFA-induced ROS generation and IR in skeletal muscle cells, which can be modulated for the management of this complex disorder.
authors.affiliation: Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032, India; Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Biology Campus, 4 Raja S. C. Mullick Road, Kolkata 700032, India.
authors.forename: Ashok
authors.initials: A
authors.lastname: Mandala
authors.affiliation: Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032, India.
authors.forename: Nabanita
authors.initials: N
authors.lastname: Das
authors.affiliation: Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032, India.
authors.forename: Sudarshan
authors.initials: S
authors.lastname: Bhattacharjee
authors.affiliation: Department of Endocrinology and Metabolism, Institute of Post Graduate Medical Education and Research, 244, A.J.C. Bose Road, Kolkata 700020, India.
authors.forename: Bidisha
authors.initials: B
authors.lastname: Mukherjee
authors.affiliation: Department of Endocrinology and Metabolism, Institute of Post Graduate Medical Education and Research, 244, A.J.C. Bose Road, Kolkata 700020, India. Electronic address: satinath.mukhopadhyay@gmail.com.
authors.forename: Satinath
authors.initials: S
authors.lastname: Mukhopadhyay
authors.affiliation: Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032, India; Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Biology Campus, 4 Raja S. C. Mullick Road, Kolkata 700032, India. Electronic address: sibsankar@iicb.res.in.
authors.forename: Sib Sankar
authors.initials: SS
authors.lastname: Roy
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001693:Biological Transport, Active / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D011345:Fenofibrate / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007333:Insulin Resistance; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D019308:Palmitic Acid / Q000494:pharmacology*; D010666:Phenylpropionates / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002352:Carrier Proteins; D005230:Fatty Acids, Nonesterified; D051275:Glucose Transporter Type 4; C506001:Mlxipl protein, mouse; D009687:Nuclear Proteins; D010666:Phenylpropionates; D011758:Pyrroles; D017382:Reactive Oxygen Species; C495693:Slc2a4 protein, mouse; D014157:Transcription Factors; C445672:Txnip protein, mouse; D019308:Palmitic Acid; D013879:Thioredoxins; C000588741:saroglitazar; D055372:AMP-Activated Protein Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D005947:Glucose; D011345:Fenofibrate
keywords: FFA; Insulin resistance; PPARα agonists; ROS; Thioredoxin interacting protein