Berberine reduces endoplasmic reticulum stress and improves insulin signal transduction in Hep G2 cells.
OBJECTIVE
Endoplasmic reticulum (ER) stress plays an important role in the pathogenesis of insulin resistance and pancreatic beta-cell dysfunction. The aim of this study is to investigate whether the insulin-sensitizing action of berberine is related to reducing ER stress.


METHODS
ER stress in cultured Hep G2 cells was induced with tunicamycin. Cells were pretreated with berberine in combination with or without insulin. The concentration of glucose was measured by glucose oxidase method. The molecular markers of ER stress, including ORP150, PERK, and eIF2 alpha were analyzed by Western blot or real time PCR. The activity of JNK was also evaluated. Moreover, the insulin signaling proteins such as IRS-1 and AKT were determined by Western blot.


RESULTS
The production of glucose stimulated with insulin was reduced. The expressions of ORP150 was decreased both in gene and protein levels when cells were pretreated with berberine, while the activation of JNK was blocked. The levels of phosphorylation both on PERK and eIF2 alpha were inhibited in cells pretreated with berberine. The level of IRS-1 ser(307) phosphorylation was decreased, whereas IRS-1 tyr phosphorylation was increased notablely. AKT ser(473) phosphorylation was also enhanced significantly in the presence of berberine.


CONCLUSIONS
The antidiabetic effect of berberine in Hep G2 cells maybe related to attenuation of ER stress and improvement of insulin signal transduction.
Wang
Zeng-si
ZS
Institute of Integrative Traditional Chinese & Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China.
Lu
Fu-er
FE
Xu
Li-jun
LJ
Dong
Hui
H
D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D001599:Berberine / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D015398:Signal Transduction / Q000187:drug effects*; D014415:Tunicamycin / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D000998:Antiviral Agents; D007328:Insulin; D001599:Berberine; D014415:Tunicamycin; D005947:Glucose
Diabetes. 2008 May;57(5):1414-8
18285556
Cell. 2009 Mar 20;136(6):1073-84
19303850
Diabetes. 2002 May;51(5):1618-21
11978664
Diabetes. 2005 Jul;54(7):1942-8
15983193
Curr Med Chem. 2003 Jan;10(2):123-53
12570714
Metabolism. 2007 Mar;56(3):405-12
17292731
J Clin Invest. 2001 Jul;108(1):41-50
11435456
Diabetes. 2005 Mar;54(3):657-63
15734840
Endocr Rev. 2008 Feb;29(1):42-61
18048764
Nat Med. 2001 Aug;7(8):947-53
11479628
Physiol Rev. 2007 Apr;87(2):507-20
17429039
J Biol Chem. 1997 Oct 24;272(43):26972-7
9341134
Am J Physiol Cell Physiol. 2007 Jan;292(1):C353-61
16971492
Science. 2004 Oct 15;306(5695):457-61
15486293
Acta Pharmacol Sin. 2004 Apr;25(4):496-502
15066220
Nature. 2001 Dec 13;414(6865):799-806
11742412
Surgery. 2005 Aug;138(2):342-51
16153446
J Biol Chem. 1996 Mar 1;271(9):5025-32
8617779
J Clin Invest. 2008 Jan;118(1):316-32
18060040
Nat Med. 2004 Dec;10(12):1344-51
15531889
World J Gastroenterol. 2008 Feb 14;14(6):876-83
18240344
Diabetes. 1999 May;48(5):1198-214
10331429
Science. 2006 Aug 25;313(5790):1137-40
16931765
Hepatology. 2002 Sep;36(3):592-601
12198651
Metabolism. 2002 Nov;51(11):1439-43
12404195
Cell Metab. 2006 Jun;3(6):417-27
16753577
J Biol Chem. 2000 Mar 24;275(12):9047-54
10722755
J Clin Invest. 2000 Jul;106(2):171-6
10903330
J Biol Chem. 2005 Jan 7;280(1):847-51
15509553
Diabetes. 2008 Mar;57(3):737-45
18065517
J Clin Invest. 2005 May;115(5):1111-9
15864338
Nature. 2002 Nov 21;420(6913):333-6
12447443
J Clin Invest. 2000 Jul;106(2):165-9
10903329
J Biol Chem. 2006 Aug 25;281(34):24336-44
16803882
Diabetes. 2006 Aug;55(8):2256-64
16873688