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Microsomal Triglyceride Transfer Protein (MTP) in the Pancreas Maintains Lipid Homeostasis, Pancreatic Function and Metabolic Health : = A Susceptibility Study of Genetic Predisposition, Lifestyle and Environmental Factors.

Record Type:	Language materials, manuscript : Monograph/item
Title/Author:	Microsomal Triglyceride Transfer Protein (MTP) in the Pancreas Maintains Lipid Homeostasis, Pancreatic Function and Metabolic Health :/
Reminder of title:	A Susceptibility Study of Genetic Predisposition, Lifestyle and Environmental Factors.
Author:	de Guzman, Hazel Consunji.
Description:	1 online resource (146 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 85-12, Section: B.
Contained By:	Dissertations Abstracts International85-12B.
Subject:	Toxicology. -
Online resource:	click for full text (PQDT)
ISBN:	9798383161128

Microsomal Triglyceride Transfer Protein (MTP) in the Pancreas Maintains Lipid Homeostasis, Pancreatic Function and Metabolic Health : = A Susceptibility Study of Genetic Predisposition, Lifestyle and Environmental Factors.
de Guzman, Hazel Consunji.

Microsomal Triglyceride Transfer Protein (MTP) in the Pancreas Maintains Lipid Homeostasis, Pancreatic Function and Metabolic Health :A Susceptibility Study of Genetic Predisposition, Lifestyle and Environmental Factors. - 1 online resource (146 pages)

Source: Dissertations Abstracts International, Volume: 85-12, Section: B.

Thesis (Ph.D.)--New York University, 2024.

Includes bibliographical references

The microsomal triglyceride transfer protein (MTP) is a multifunctional lipid binding and transfer protein. It is highly expressed in the intestine and in the liver where it is essential for ApoB-lipoprotein (Blps) secretion. Loss-of-function mutation of MTP in abetalipoproteinemia (ABL) presents with a general failure to thrive in infancy due to malabsorption of fats and fat-soluble vitamins. Tissue-specific knockout of MTP in mice has shown lipid accumulation in the intestine, liver, heart, eyes and kidneys, suggesting that MTP protects against lipid accumulation. We hypothesized that MTP plays a similar protective role in the pancreas. We observed that MTP is expressed at comparatively lower levels in the acinar cells of pancreas. We generated an acinar cell-specific MTP knockout (AcKO) mouse model by breeding mice having the floxed MTP allele (Mttpf/f) with transgenic Cela1-cre mice. We maintained male and female AcKO and Mttpf/f mice on regular diet for 12-13 months and monitored biochemical and physiologic parameters. We observed that lipids, particularly cholesterol, accumulated in different subcellular fractions of the pancreas of male and female AcKO mice. In both cases there were disruptions in the processing of digestive enzymes and lipid malabsorption. The AcKO mice increased their food intake and insulin sensitivity likely to compensate for malabsorption. However, frequent feeding or pancreatic microenvironment changes could have led to beta cell overstimulation and hypersecretion. The chronic exposure to relatively high insulin levels may have desensitized the peripheral tissues, leading to increased insulin resistance in the AcKO towards the end of the experiment, which was more pronounced in the males. The female AcKO were able to better regulate their glucose and lipid metabolism, reflecting sex-biased adaptations to lipid-induced stress and nutritional challenges. We then hypothesized that pancreatic MTP deficiency will be more prone to pancreatic damage and dysfunction with high fat diet and alcohol. We placed 6-month-old male AcKO and Mttpf/f mice on a high fat diet for 1 month then orally administered 3 mg/kg ethanol or water for 5 consecutive days. Pancreatic injury and plasma C-reactive protein levels tended to be higher in the AcKO mice compared to the control mice. Our study demonstrated for the first time that MTP in the pancreas plays a role in maintaining lipid homeostasis that is vital for optimal exocrine and endocrine functions. This has implications for overall metabolic health.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2024

Mode of access: World Wide Web

ISBN: 9798383161128Subjects--Topical Terms:

580973
Toxicology.
Subjects--Index Terms:

AlcoholIndex Terms--Genre/Form:

554714
Electronic books.

Microsomal Triglyceride Transfer Protein (MTP) in the Pancreas Maintains Lipid Homeostasis, Pancreatic Function and Metabolic Health : = A Susceptibility Study of Genetic Predisposition, Lifestyle and Environmental Factors.
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520 $a The microsomal triglyceride transfer protein (MTP) is a multifunctional lipid binding and transfer protein. It is highly expressed in the intestine and in the liver where it is essential for ApoB-lipoprotein (Blps) secretion. Loss-of-function mutation of MTP in abetalipoproteinemia (ABL) presents with a general failure to thrive in infancy due to malabsorption of fats and fat-soluble vitamins. Tissue-specific knockout of MTP in mice has shown lipid accumulation in the intestine, liver, heart, eyes and kidneys, suggesting that MTP protects against lipid accumulation. We hypothesized that MTP plays a similar protective role in the pancreas. We observed that MTP is expressed at comparatively lower levels in the acinar cells of pancreas. We generated an acinar cell-specific MTP knockout (AcKO) mouse model by breeding mice having the floxed MTP allele (Mttpf/f) with transgenic Cela1-cre mice. We maintained male and female AcKO and Mttpf/f mice on regular diet for 12-13 months and monitored biochemical and physiologic parameters. We observed that lipids, particularly cholesterol, accumulated in different subcellular fractions of the pancreas of male and female AcKO mice. In both cases there were disruptions in the processing of digestive enzymes and lipid malabsorption. The AcKO mice increased their food intake and insulin sensitivity likely to compensate for malabsorption. However, frequent feeding or pancreatic microenvironment changes could have led to beta cell overstimulation and hypersecretion. The chronic exposure to relatively high insulin levels may have desensitized the peripheral tissues, leading to increased insulin resistance in the AcKO towards the end of the experiment, which was more pronounced in the males. The female AcKO were able to better regulate their glucose and lipid metabolism, reflecting sex-biased adaptations to lipid-induced stress and nutritional challenges. We then hypothesized that pancreatic MTP deficiency will be more prone to pancreatic damage and dysfunction with high fat diet and alcohol. We placed 6-month-old male AcKO and Mttpf/f mice on a high fat diet for 1 month then orally administered 3 mg/kg ethanol or water for 5 consecutive days. Pancreatic injury and plasma C-reactive protein levels tended to be higher in the AcKO mice compared to the control mice. Our study demonstrated for the first time that MTP in the pancreas plays a role in maintaining lipid homeostasis that is vital for optimal exocrine and endocrine functions. This has implications for overall metabolic health.
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