Glucagon and the Heart

Farah, A.

doi:10.1007/978-3-642-69019-8_31

Cited by 50 publications

(60 citation statements)

References 267 publications

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“…In contrast to suspension cultures, collagen sandwich culture morphologically and functionally mimics events in vivo (31,32). The culture medium contains insulin (0.02 mg/mL) and glucagon (0.0284 μg/mL), which increase cAMP (34,35); however, taurocholate and forskolin significantly increased cAMP compared with control cells. The mechanism by which taurocholate increases cAMP in collagen sandwich cultures may involve an unknown G protein-coupled receptor (36).…”

Section: Discussionmentioning

confidence: 99%

Bile acid stimulates hepatocyte polarization through a cAMP-Epac-MEK-LKB1-AMPK pathway

Wakabayashi

Lippincott‐Schwartz

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

125

115

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This study describes a unique function of taurocholate in bile canalicular formation involving signaling through a cAMP-Epac-MEK-Rap1-LKB1-AMPK pathway. In rat hepatocyte sandwich cultures, polarization was manifested by sequential progression of bile canaliculi from small structures to a fully branched network. Taurocholate accelerated canalicular network formation and concomitantly increased cAMP, which were prevented by adenyl cyclase inhibitor. The cAMP-dependent PKA inhibitor did not prevent the taurocholate effect. In contrast, activation of Epac, another cAMP downstream kinase, accelerated canalicular network formation similar to the effect of taurocholate. Inhibition of Epac downstream targets, Rap1 and MEK, blocked the taurocholate effect. Taurocholate rapidly activated MEK, LKB1, and AMPK, which were prevented by inhibition of adenyl cyclase or MEK. Our previous study showed that activated-LKB1 and AMPK participate in canalicular network formation. Linkage between bile acid synthesis, hepatocyte polarization, and regulation of energy metabolism is likely important in normal hepatocyte development and disease.primary hepatocytes | occludin | P-glycoprotein H epatocytes, the major epithelial cells in the liver, are polarized. Tight junction proteins, including occludin, claudin, and ZO-1, seal the canalicular lumen, thereby separating apical and basolateral membrane domains and forming the bile canaliculus (1). Polarization is essential for biliary secretion. The mechanisms of polarization are complex and include cytoskeletal, tight junctional, and intracellular trafficking components (2-5). Loss of polarity causes bile secretory failure (cholestasis) and liver damage (6).Bile acids are synthesized from cholesterol in hepatocytes, secreted by ABCB11 (Bsep) into the bile canaliculus, and then mostly absorbed into the enterohepatic circulation (7). The major bile acids in mammals are tauro or glycine conjugates of cholic, deoxycholic, and chenodeoxycholic acids (8). In addition to their traditional function in emulsification of dietary fat (8), recent studies reveal that bile acids function as signaling molecules (9), which increase calcium mobilization (10) and cellular cAMP (9); translocate and activate protein kinase C (11), nuclear farnesoid X receptor (FXR), and pregnane X receptors (PXR) (7, 9); activate PI3K/AKT/glycogen synthase kinase 3 (GSK3) (12); and enhance liver regeneration (13).During embryonic development, early fetal hepatocytes are not polarized (14-16). In fetal mice and rats, infrequent small canaliculi are present, but do not attain an adult appearance until several days postpartum (17). Bile acid synthesis, turnover, and secretion are sparse in fetal liver, and rapidly increase postnatally (18,19), concomitant with hepatocyte polarization and development of a branched canalicular network. Based on these events, we postulated that bile acids may regulate hepatocyte polarization and canalicular formation. Using collagen sandwich cultures of rat primary hepatocytes, we confirmed this hy...

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Section: Discussionmentioning

confidence: 99%

Bile acid stimulates hepatocyte polarization through a cAMP-Epac-MEK-LKB1-AMPK pathway

Wakabayashi

Lippincott‐Schwartz

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

125

115

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“…Glucagon is also able to directly stimulate insulin release (Samols et al, 1966) through its own receptors expressed on pancreatic ␤-cells (Kawai et al, 1995;Moens et al, 1998). Although more likely pharmacological than physiological, glucagon administration produces positive inotropic and chronotropic effects on the heart (Farah, 1983), exerts spasmolytic effects on gastrointestinal smooth muscle (Diamant and Picazo, 1983) and growth hormone-releasing activities (Merimee, 1983).…”

Section: B Biological Activitiesmentioning

confidence: 99%

International Union of Pharmacology. XXXV. The Glucagon Receptor Family

et al. 2003

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“…In adult animals glucagon is known to cause vasodilation in the splanchnic bed (for review see Farah, 1983). It seems that glucagon infusion in the fetus also induces a decrease in the vascular resistance of the splanchnic bed.…”

Section: Perina Tal Hepa Tic Gl Ycogenol Ysis In Vivomentioning

confidence: 99%

Release of glucose from the liver of fetal and postnatal sheep by portal vein infusion of catecholamines or glucagon.

Apatu

Barnes

1991

The Journal of Physiology

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SUMMARY1. The blood flow to the liver in fetuses near term, newborn and adult sheep was measured by the Fick principle, using radionuclide-labelled plastic microspheres, before and during infusion of adrenaline, noradrenaline or glucagon.2. Glucose output and lactate consumption by the liver in sheep of each age group were calculated by application of the Fick principle using the concentration gradients of these metabolites measured in blood samples obtained, simultaneously with blood flow measurements, from catheters chronically implanted in the inflow and outflow vessels of the liver.3. Catecholamines were infused into the portal vein of fetuses near term at a rate comparable with that at which they are known to be secreted in the sheep fetus during moderate to severe hypoxia. The cardiovascular and metabolic responses to these infusions were found to be comparable with those that occur in the fetus during hypoxia.4. Catecholamines increased glucose output from the liver in all except the immediate post-partum animals. Catecholamines were less effective than glucagon in promoting glucose release. The mean increments in glucose output during adrenaline infusion were 0055+0-015 mmol min-(100 g liver)-1 in the fetus, 0-122+ 0024 mmol min-(100 g)-1 in the 2-week-old lambs, 0078+0019 mmol min-' (100 g)-' in young lambs and 0-049+0-012 mmol min-' (100 g)-' in the adult sheep.During glucagon infusion the mean glucose output increments were 0-146 + 0023 mmol min-1 (100 g)-in the fetus, 0-274+0-085 mmol min-(100 g)-1 in the 2-week-old and young lambs and 0 180+0-054 mmol min-' (100 g)-1 in the adult. Adrenaline was more potent than noradrenaline, suggesting that the major glycogenolytic response might be f-receptor mediated.5. In the immediate newborn period the output of glucose from the liver was high (0-20 + 0-05 mmol min-' (100 g liver)-' and was not statistically significantly increased by infusion either of glucagon or of catecholamines which resulted in similar increments of glucose output of about 04128 +0-133 mmol min-' (100 g)-1. It is probable that the high output of glucose reflected the high endogenous circulating levels of catecholamines and glucagon in these animals at birth and that further infusions failed to add significantly to the already near-maximal glucose release. R. S. K. APATU AND R. J. BARNES absence of high levels of circulating catecholamines and glucagon in the resting fetus but also may indicate a deficiency in either the receptor mechanism for catecholamines or of the intracellular second messenger system for glycogenolysis. The greater effectiveness of glucagon (than adrenaline) as a mediator of glucose release in these animals tends to support the idea of a fl-receptor rather than a second messenger deficiency. It is postulated that a deficiency of hepatic ,-adrenergic receptors, provided that it can be corrected in time for birth, would help to protect glycogen stores in the liver in utero.

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Glucagon and the Heart

Cited by 50 publications

References 267 publications

Bile acid stimulates hepatocyte polarization through a cAMP-Epac-MEK-LKB1-AMPK pathway

Bile acid stimulates hepatocyte polarization through a cAMP-Epac-MEK-LKB1-AMPK pathway

International Union of Pharmacology. XXXV. The Glucagon Receptor Family

Release of glucose from the liver of fetal and postnatal sheep by portal vein infusion of catecholamines or glucagon.

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