title: Fucosterol activates the insulin signaling pathway in insulin resistant HepG2 cells via inhibiting PTP1B.
abstract: Insulin resistance is a characteristic feature of type 2 diabetes mellitus (T2DM) and is characterized by defects in insulin signaling. This study investigated the modulatory effects of fucosterol on the insulin signaling pathway in insulin-resistant HepG2 cells by inhibiting protein tyrosine phosphatase 1B (PTP1B). In addition, molecular docking simulation studies were performed to predict binding energies, the specific binding site of fucosterol to PTP1B, and to identify interacting residues using Autodock 4.2 software. Glucose uptake was determined using a fluorescent D-glucose analogue and the glucose tracer 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxyglucose, and the signaling pathway was detected by Western blot analysis. We found that fucosterol enhanced insulin-provoked glucose uptake and conjointly decreased PTP1B expression level in insulin-resistant HepG2 cells. Moreover, fucosterol significantly reduced insulin-stimulated serine (Ser307) phosphorylation of insulin receptor substrate 1 (IRS1) and increased phosphorylation of Akt, phosphatidylinositol-3-kinase, and extracellular signal- regulated kinase 1 at concentrations of 12.5, 25, and 50 µM in insulin-resistant HepG2 cells. Fucosterol inhibited caspase-3 activation and nuclear factor kappa B in insulin-resistant hepatocytes. These results suggest that fucosterol stimulates glucose uptake and improves insulin resistance by downregulating expression of PTP1B and activating the insulin signaling pathway. Thus, fucosterol has potential for development as an anti-diabetic agent.
authors.affiliation: Department of Food Science and Human Nutrition, Chonbuk National University, Jeonju, 561-756, Republic of Korea.
authors.forename: Hyun Ah
authors.initials: HA
authors.lastname: Jung
authors.affiliation: Department of Food and Life Science, Pukyong National University, Busan, 608-737, Republic of Korea.
authors.forename: Himanshu Kumar
authors.initials: HK
authors.lastname: Bhakta
authors.affiliation: College of Pharmacy, Catholic University of Daegu, Gyeongsan, 712-702, Republic of Korea.
authors.forename: Byung-Sun
authors.initials: BS
authors.lastname: Min
authors.affiliation: Department of Food and Life Science, Pukyong National University, Busan, 608-737, Republic of Korea. choijs@pknu.ac.kr.
authors.forename: Jae Sue
authors.initials: JS
authors.lastname: Choi
mesh_terms: D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D056945:Hep G2 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013265:Stigmasterol / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D007328:Insulin; C015896:fucosterol; D013265:Stigmasterol; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1
keywords: Antdiabetic; Fucosterol; Glucose uptake; HepG2 cell; Molecular docking; Protein tyrosine phosphatase 1B