A Novel Mechanism for Regulating Hepatic Glycogen Synthesis Involving Serotonin and Cyclin-Dependent Kinase-5

Abstract

Hepatic autonomic nerves regulate postprandial hepatic glucose uptake, but the signaling pathways remain unknown. We tested the hypothesis that serotonin (5-hydroxytryptamine [5-HT]) exerts stimulatory and inhibitory effects on hepatic glucose disposal. Ligands of diverse 5-HT receptors were used to identify signaling pathway(s) regulating glucose metabolism in hepatocytes. 5-HT had stimulatory and inhibitory effects on glycogen synthesis in hepatocytes mediated by 5-HT1/2A and 5-HT2B receptors, respectively. Agonists of 5-HT1/2A receptors lowered blood glucose and increased hepatic glycogen after oral glucose loading and also stimulated glycogen synthesis in freshly isolated hepatocytes with greater efficacy than 5-HT. This effect was blocked by olanzapine, an antagonist of 5-HT1/2A receptors. It was mediated by activation of phosphorylase phosphatase, inactivation of glycogen phosphorylase, and activation of glycogen synthase. Unlike insulin action, it was not associated with stimulation of glycolysis and was counteracted by cyclin-dependent kinase (cdk) inhibitors. A role for cdk5 was supported by adaptive changes in the coactivator protein p35 and by elevated glycogen synthesis during overexpression of p35/cdk5. These results support a novel mechanism for serotonin stimulation of hepatic glycogenesis involving cdk5. The opposing effects of serotonin, mediated by distinct 5-HT receptors, could explain why drugs targeting serotonin function can cause either diabetes or hypoglycemia in humans.

L-Tryptophan Suppresses Rise in Blood Glucose and Preserves Insulin Secretion in Type-2 Diabetes Mellitus Rats

“…Although the ratio of NADH/NAD 1 is important for glucose metabolism (31), the amount of NADH itself also regulated them, because GAPDH activity was inhibited by NADH attachment (32). Thus, de novo NAD 1 synthesis from l-tryptophan possibly participated in upregulation of glycogen synthesis (29).…”

Cdks, cyclins and CKIs: roles beyond cell cycle regulation

“…Hepatocytes are widely used in these analyses, as the liver is a hub of numerous metabolic pathways, including glycogenesis and lipogenesis. During liver glycogen synthesis, Cdk5/p35 (Cdk5r1) was found to be an intermediary component of the signaling cascade that transduces serotonin [5-hydroxytryptamine (5-HT)] stimulation of 5-HT receptors to the activation of glycogen synthase, an enzyme that polymerizes glucose to form glycogen (Tudhope et al, 2012). Lipid biosynthesis is stimulated by insulin and results in downstream activation of the transcription factor Srebp-1c (Srebf1).…”

Role of Serotonin in the Regulation of Respiration and Bile Secretory Function of the Liver

“…Слід відзначити, що із семи родин серотонінових рецепторів у різних клітинних популяціях печінки найбільш інтенсивно експресуються 5-НТ 2 -рецепто-ри, які опосередковують вплив аутокоїда на метаболічні та регенеративні процеси в тканині цього органа [6][7][8][9]. Нині більшість досліджень гепатотропних ефектів серото-ніну спрямовані на з'ясування його дії на регенерацію і канцерогенез у печінковій тканині [10].…”

“…Як зазначалось вище, із семи родин серо-тонінових рецепторів, виявлених у печінці, найбільш інтенсивно експресуються і, до того ж, опосередковують дію серотоніну на мета-болічні процеси в залозі 5-НТ 2 -рецептори [6,9]. Тому ми вирішили з'ясувати їхню роль у реалізації стимулювальної дії серотоніну на тканинне дихання печінки.…”