Role of Group 1B Phospholipase A2 in Diet-induced Hyperlipidemia and Selected Disorders of Lipid Metabolism

Role of Group 1B Phospholipase A2 in Diet-induced Hyperlipidemia and Selected Disorders of Lipid Metabolism

Bibliographic Details
Main Author: Hollie, Norris I., II
Language:English
Published: University of Cincinnati / OhioLINK 2013
Subjects:
Pathology
Group IB Phospholipase A2
Lysophosphatidylcholine
Lipoprotein
Liver
Oxidation
Hyperlipidemia
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=ucin1378112803
id ndltd-OhioLink-oai-etd.ohiolink.edu-ucin1378112803
record_format oai_dc
collection NDLTD
language English
sources NDLTD
topic Pathology
Group IB Phospholipase A2
Lysophosphatidylcholine
Lipoprotein
Liver
Oxidation
Hyperlipidemia
spellingShingle Pathology
Group IB Phospholipase A2
Lysophosphatidylcholine
Lipoprotein
Liver
Oxidation
Hyperlipidemia
Hollie, Norris I., II
Role of Group 1B Phospholipase A2 in Diet-induced Hyperlipidemia and Selected Disorders of Lipid Metabolism
author Hollie, Norris I., II
author_facet Hollie, Norris I., II
author_sort Hollie, Norris I., II
title Role of Group 1B Phospholipase A2 in Diet-induced Hyperlipidemia and Selected Disorders of Lipid Metabolism
title_short Role of Group 1B Phospholipase A2 in Diet-induced Hyperlipidemia and Selected Disorders of Lipid Metabolism
title_full Role of Group 1B Phospholipase A2 in Diet-induced Hyperlipidemia and Selected Disorders of Lipid Metabolism
title_fullStr Role of Group 1B Phospholipase A2 in Diet-induced Hyperlipidemia and Selected Disorders of Lipid Metabolism
title_full_unstemmed Role of Group 1B Phospholipase A2 in Diet-induced Hyperlipidemia and Selected Disorders of Lipid Metabolism
title_sort role of group 1b phospholipase a2 in diet-induced hyperlipidemia and selected disorders of lipid metabolism
publisher University of Cincinnati / OhioLINK
publishDate 2013
url http://rave.ohiolink.edu/etdc/view?acc_num=ucin1378112803
work_keys_str_mv AT hollienorrisiii roleofgroup1bphospholipasea2indietinducedhyperlipidemiaandselecteddisordersoflipidmetabolism
_version_ 1719434821258706944
spelling ndltd-OhioLink-oai-etd.ohiolink.edu-ucin13781128032021-08-03T06:19:39Z Role of Group 1B Phospholipase A2 in Diet-induced Hyperlipidemia and Selected Disorders of Lipid Metabolism Hollie, Norris I., II Pathology Group IB Phospholipase A2 Lysophosphatidylcholine Lipoprotein Liver Oxidation Hyperlipidemia As obesity rates increase in developed nations, the prevalence of other obesity-related metabolic disorders such as hyperlipidemia, atherosclerosis, and non-alcoholic fatty liver disease (NAFLD) has also increased drastically. A greater understanding of the pathobiology and molecular mechanisms of these disorders becomes increasingly relevant. Recent studies demonstrated that certain alleles of the pancreatic group 1B phospholipase A2 (PLA2G1B) are associated with increased obesity and that Pla2g1b-deficient (Pla2g1b-/-) mice are protected against diet-induced obesity and diabetes. Furthermore, supplying mice with lysophosphatidylcholine (LPC), the enzymatic product of Pla2g1b, causes hyperglycemia and insulin resistance, which are risk factors for hyperlipidemia, atherosclerosis, and NAFLD. Thus, Pla2g1b may play a role in the development of these obesity-related diseases and inhibiting Pla2g1b and/or LPC may change the progression of these metabolic disorders. The goal of the first part of this dissertation was to identify a Pla2g1b-mediated protection against hyperlipidemia. Findings from these studies indicate that Pla2g1b-/- mice are protected against high fat diet-induced hyperlipidemia and gain less weight than Pla2g1b+/+ controls due to decreased very-low-density lipoprotein (VLDL) production and increased postprandial triglyceride-rich lipoprotein clearance. Further results indicate that supplying LPC stimulates VLDL production in both Pla2g1b-/- and Pla2g1b+/+ mice and that LPC is directly used as a substrate to make VLDL-triglyceride (TG). Taken together, these findings indicate that inhibition of luminal Pla2g1b may be a viable strategy to decrease hyperlipidemia in vivo.The goal of the second part of this dissertation was to identify a mechanism of LPC-mediated inhibition of hepatic oxidative function. Pla2g1b-/- mice have decreased plasma LPC and increased hepatic oxidation that is inhibited by intraperitoneal injection of LPC by an unknown mechanism. Findings indicate that though low micromolar concentrations of LPC decrease the mitochondrial membrane potential, oxidation rate remains equal to controls up to incubation with 80 µM LPC. However, when isolated mitochondria or hepatocytes are supplied with 100 µM LPC, decreased substrate-stimulated oxidation and increased mitochondrial permeability are observed. These findings indicate that LPC plays a major role in the maintenance of hepatic mitochondrial integrity and function and that low micromolar changes in intra- and extracellular LPC concentration can greatly affect hepatic oxidation rate.The goal of the third part of this dissertation was to identify a Pla2g1b-mediated protection against atherosclerosis and NAFLD. Findings indicate decreased obesity, VLDL-TG, VLDL-cholesterol, low-density lipoprotein-cholesterol, and hepatomegaly in Pla2g1b-/-/Ldlr-/- mice compared to Pla2g1b+/+/Ldlr-/- controls. Findings also suggested decreased atherosclerotic lesion size in Pla2g1b-/-/Ldlr-/- mice.Taken together, the findings from this dissertation have three implications in the field of metabolic research. First, these studies indicate a vital role for Pla2g1b and LPC in modulating hepatic function. Regardless of the Pla2g1b status of experimental animals, the mechanisms of LPC action appear intact. Secondly, these studies indicate that inhibition of Pla2g1b provides protection against diet-induced obesity in two diverse murine models. Thirdly, decreased VLDL-TG is described as a hallmark of inhibition of Pla2g1b. The development of a single drug to inhibit the action of PLA2G1B would likely lead to improvements in obesity, diabetes, hyperlipidemia, and potentially atherosclerosis. 2013-09-16 English text University of Cincinnati / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ucin1378112803 http://rave.ohiolink.edu/etdc/view?acc_num=ucin1378112803 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.

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