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Gut Hormone Regulation of Hepatic an...

Hoffman, Simon Steinbring.

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Gut Hormone Regulation of Hepatic and Intestinal Lipoprotein Production.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Gut Hormone Regulation of Hepatic and Intestinal Lipoprotein Production./
作者:	Hoffman, Simon Steinbring.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2023,
面頁冊數:	212 p.
附註:	Source: Dissertations Abstracts International, Volume: 85-01, Section: B.
Contained By:	Dissertations Abstracts International85-01B.
標題:	Physiology. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30420480
ISBN:	9798379763503

Gut Hormone Regulation of Hepatic and Intestinal Lipoprotein Production.
Hoffman, Simon Steinbring.

Gut Hormone Regulation of Hepatic and Intestinal Lipoprotein Production. - Ann Arbor : ProQuest Dissertations & Theses, 2023 - 212 p.

Source: Dissertations Abstracts International, Volume: 85-01, Section: B.

Thesis (Ph.D.)--University of Toronto (Canada), 2023.

Dyslipidemia is a key component of insulin resistance, which results in the overproduction of hepatic and intestinal apolipoprotein (apo)B-containing lipoprotein particles. These particles are catabolized down into highly proatherogenic remnants. Several gut-derived peptides have been identified as regulators of energy metabolism; one such peptide is the incretin hormone glucagon-like peptide (GLP)-1. Our laboratory has previously demonstrated that GLP-1 can signal both centrally and peripherally to reduce postprandial and fasting lipoprotein secretion. Here, I examine a novel vagal neuroendocrine signalling pathway by which native GLP-1 may exert its anti-lipemic effects. Furthermore, I demonstrate a novel role for other gut-derived peptides in regulating intestinal lipoprotein production. Portal vein injections of GLP-1(7-36) into Syrian golden hamsters revealed a site-specific anti-lipemic role for native GLP-1. This effect was lost after GLP-1R antagonism, and in a GLP-1R KO hamster model. The suppressive effects of portal GLP-1 on intestinal lipoprotein excursion were also lost after chemical, pharmacological, surgical, or selective denervation of the vagus nerve - together identifying the vagus nerve as a key component of GLP-1's endogenous signalling pathway. Moreover, we demonstrate a role for nodose ganglia GLP-1R-containing neurons in propagating anti-lipemic viscerosensory signals. These data are complimented by the finding of portal and nodose ganglia GLP-1 resistance following diet-induced insulin resistance, suggesting loss of this vagal GLP-1 signalling pathway may occur at the advent of diabetic dyslipidemia. The role of other gut- derived anorexigenic hormones were also investigated, and we identified that Peptide YY, oxytocin, and cholecystokinin (CCK) also exert a suppressive effect on postprandial lipoprotein metabolism. Importantly, we also delineate the effect of CCK receptor signalling from bile acid release on postprandial lipemia. This in combination with data showing CCKs effects are lost in GLP-1R KO hamsters suggests that CCK may exert its effects though bile acid-mediated increases in GLP-1 secretion. Overall, the data presented here supports a key role for GLP-1 receptors on the portal vein afferent neurons in modulating intestinal fat absorption and lipoprotein production and identifies other gut-derived peptides as novel regulators of postprandial lipemia. Insights from these data may support identification of potential drug targets for treatment of diabetic dyslipidemia.

ISBN: 9798379763503Subjects--Topical Terms:

518431
Physiology.
Subjects--Index Terms:

Chylomicron

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520 $a Dyslipidemia is a key component of insulin resistance, which results in the overproduction of hepatic and intestinal apolipoprotein (apo)B-containing lipoprotein particles. These particles are catabolized down into highly proatherogenic remnants. Several gut-derived peptides have been identified as regulators of energy metabolism; one such peptide is the incretin hormone glucagon-like peptide (GLP)-1. Our laboratory has previously demonstrated that GLP-1 can signal both centrally and peripherally to reduce postprandial and fasting lipoprotein secretion. Here, I examine a novel vagal neuroendocrine signalling pathway by which native GLP-1 may exert its anti-lipemic effects. Furthermore, I demonstrate a novel role for other gut-derived peptides in regulating intestinal lipoprotein production. Portal vein injections of GLP-1(7-36) into Syrian golden hamsters revealed a site-specific anti-lipemic role for native GLP-1. This effect was lost after GLP-1R antagonism, and in a GLP-1R KO hamster model. The suppressive effects of portal GLP-1 on intestinal lipoprotein excursion were also lost after chemical, pharmacological, surgical, or selective denervation of the vagus nerve - together identifying the vagus nerve as a key component of GLP-1's endogenous signalling pathway. Moreover, we demonstrate a role for nodose ganglia GLP-1R-containing neurons in propagating anti-lipemic viscerosensory signals. These data are complimented by the finding of portal and nodose ganglia GLP-1 resistance following diet-induced insulin resistance, suggesting loss of this vagal GLP-1 signalling pathway may occur at the advent of diabetic dyslipidemia. The role of other gut- derived anorexigenic hormones were also investigated, and we identified that Peptide YY, oxytocin, and cholecystokinin (CCK) also exert a suppressive effect on postprandial lipoprotein metabolism. Importantly, we also delineate the effect of CCK receptor signalling from bile acid release on postprandial lipemia. This in combination with data showing CCKs effects are lost in GLP-1R KO hamsters suggests that CCK may exert its effects though bile acid-mediated increases in GLP-1 secretion. Overall, the data presented here supports a key role for GLP-1 receptors on the portal vein afferent neurons in modulating intestinal fat absorption and lipoprotein production and identifies other gut-derived peptides as novel regulators of postprandial lipemia. Insights from these data may support identification of potential drug targets for treatment of diabetic dyslipidemia.
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