Mibefradil reduces hepatic glucose output in HepG2 cells via Ca2+/calmodulin-dependent protein kinase II-dependent Akt/forkhead box O1signaling

Dai, Ying; Shan, Meng-ya; Li, Peilin; Lingong, Zhao; Ma, Hongxia; Xu, Jing; Zhang, Le; Zhang, Kebin; Chen, Bin; Yan, Jun; Guo, Shaodong; Xu, Zihui

doi:10.1016/j.ejphar.2021.174296

Cited by 3 publications

(1 citation statement)

References 42 publications

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“…26) Measurement of the Intracellular Ca 2+ Concentration The intracellular Ca 2+ concentration was measured using a Ca 2+ fluorescent probe (Fluo 4-AM; Dojindo Laboratories, Co., Ltd., Kumamoto, Japan). 27,28) Hepatocytes attached to the culture dish were incubated in a recording buffer (20 mM N-(2-hydroxyethyl) piperazine-N′-2-ethanesulfonic acid (HEPES), 115 mM NaCl, 5.4 mM KCl, 0.8 mM MgCl 2 , 1.8 mM CaCl 2 , and 13.8 mM glucose) containing 3 µM Fluo 4-AM for 40 min at 37 °C. Hepatocytes were washed with PBS and then incubated in a recording buffer containing SAC for 0 to 20 min.…”

Section: Measurement Of Igf-i Secretion Into the Mediummentioning

confidence: 99%

<i>S</i>-Allyl-L-cysteine Promotes Cell Proliferation by Stimulating Growth Hormone Receptor/Janus Kinase 2/Phospholipase C Pathways and Promoting Insulin-Like Growth Factor Type-I Secretion in Primary Cultures of Adult Rat Hepatocytes

Moteki

Ogihara

Kimura

2022

Biological & Pharmaceutical Bulletin

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The mechanism of insulin-like growth factor type-I (IGF-I) secretion stimulated by S-allyl-L-cysteine (SAC) was investigated as part of a study of SAC-induced DNA synthesis and cell proliferation in primary cultures of adult rat hepatocytes. When 10 6 M SAC was added to the culture, the amount of IGF-I in the medium was significantly increased at 10 min. The peak IGF-I level (140 pg/mL) was observed 20 min after SAC stimulation. The SAC-induced IGF-I secretion was completely suppressed by a selective Janus kinase 2 (JAK2) inhibitor (TG101209), a selective phospholipase C (PLC) inhibitor (U-73122), an intracellular Ca 2 chelating agent (BAPTA-AM), and a granule secretion inhibitor (somatostatin). On the other hand, 10 6 M SAC-stimulated hepatocytes showed increased intracellular Ca 2 concentration in a time-dependent manner from 0 to 10 min. Phosphorylation of SAC-induced JAK2 and IGF-I receptor tyrosine kinase (RTK) was completely suppressed by TG101209. In addition, U-73122, BAPTA-AM, and somatostatin did not suppress SAC-induced JAK2 phosphorylation, but significantly suppressed SAC-induced IGF-I RTK phosphorylation. Furthermore, binding of the monoclonal antibody against growth hormone (GH) to GH receptor was dosedependently suppressed by SAC on immunofluorescence. These results showed that SAC promotes cell proliferation by stimulating GH receptor/JAK2/phospholipase C pathways and promoting autocrine secretion of IGF-I in primary cultures of adult rat hepatocytes.

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Section: Measurement Of Igf-i Secretion Into the Mediummentioning

confidence: 99%

<i>S</i>-Allyl-L-cysteine Promotes Cell Proliferation by Stimulating Growth Hormone Receptor/Janus Kinase 2/Phospholipase C Pathways and Promoting Insulin-Like Growth Factor Type-I Secretion in Primary Cultures of Adult Rat Hepatocytes

Moteki

Ogihara

Kimura

2022

Biological & Pharmaceutical Bulletin

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Avenanthramides Ameliorate Insulin Resistance by Modulating Gluconeogenesis and Glycogen Synthesis in HepG2 Cells

Hong,

Heo,

Kim

et al. 2024

Journal of Medicinal Food

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TRIB2-Mediated Modulation of AMPK Promotes Hepatic Insulin Resistance

Wang,

Kang,

Zhang

et al. 2024

Diabetes

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Insulin resistance and its linked health complications are increasing in prevalence. Recent work has caused the role of Tribbles2 (TRIB2) in metabolism and cellular signaling to be increasingly appreciated, but its role in the progression of insulin resistance has not been elucidated. Here, we explore the functions of TRIB2 in modulating insulin resistance and the mechanism involved in insulin resistance mice and palmitic acid (PA) treated HepG2 cells. We demonstrate that whole-body knockout and hepatic-specific TRIB2 deficiency protect against diet-induced insulin resistance, inflammation and ER stress. Accordingly, upregulation of TRIB2 in the liver aggravates these metabolic disturbances in HFD-induced mice and ob/ob mice. Mechanistically, TRIB2 directly binds to the αγ-SBS domain of PRKAB through its pseudokinase domain, subsequently inhibiting the formation and activity of the AMPK complex. Moreover, the results of intervention against AMPK suggest that the effects of TRIB2 depend on AMPK. Our findings reveal that TRIB2 is a novel target for the treatment of insulin resistance and its associated metabolic complications and clarify the function of TRIB2 as a regulatory component of AMPK activity.

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Mibefradil reduces hepatic glucose output in HepG2 cells via Ca2+/calmodulin-dependent protein kinase II-dependent Akt/forkhead box O1signaling

Cited by 3 publications

References 42 publications

<i>S</i>-Allyl-L-cysteine Promotes Cell Proliferation by Stimulating Growth Hormone Receptor/Janus Kinase 2/Phospholipase C Pathways and Promoting Insulin-Like Growth Factor Type-I Secretion in Primary Cultures of Adult Rat Hepatocytes

<i>S</i>-Allyl-L-cysteine Promotes Cell Proliferation by Stimulating Growth Hormone Receptor/Janus Kinase 2/Phospholipase C Pathways and Promoting Insulin-Like Growth Factor Type-I Secretion in Primary Cultures of Adult Rat Hepatocytes

Avenanthramides Ameliorate Insulin Resistance by Modulating Gluconeogenesis and Glycogen Synthesis in HepG2 Cells

TRIB2-Mediated Modulation of AMPK Promotes Hepatic Insulin Resistance

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