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Identification and characterization of the biochemical and physiological functions of Acyl-CoA dehydrogenase 10

Kormanik, Kaitlyn (2014) Identification and characterization of the biochemical and physiological functions of Acyl-CoA dehydrogenase 10. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

The acyl-CoA dehydrogenase, ACAD, genes encode enzymes that are essential to cellular metabolism as evidenced by the identification in the past 20 years of genetic defects associated with nine members of this gene family. In total, these defects constitute the most common inborn errors of metabolism identified through newborn screening and so are concerns to public health. Recently, two new ACADs, ACAD10 and 11, of unknown function have been identified. This discovery raises the specter of additional unrecognized disorders since prior studies on these two ACADs suggested a novel role in metabolism. Recently, ACAD10 has been linked to type 2 diabetes in Pima Indians, which draws additional attention to its role in metabolism and public health importance.
Both ACAD10 and ACAD11 are highly conserved but with unique additional large protein domains compared to other ACADs, likely encoded from multiple coding domains. ACAD10 antigen in mice is present in lung, muscle, kidney, and pancreas, and localized to mitochondria, while a weak signal is also observed in peroxisomes of mouse lung. Human tissues including lung, kidney, liver, muscle, and pancreas reveal antigen present in mitochondria, and a weak antigen signal in peroxisomes in kidney and pancreas.
To investigate the role of ACAD10 in metabolism further, I have generated an Acad10 deficient mouse and have characterized it through pathological, biochemical, and molecular studies. Deficient animals are viable and fertile, but become obese. Pathological studies reveal inflammatory liver disease and secondary splenic extramedullary hematopoiesis. Skeletal muscle findings were abnormal , consistent with deficient mice have elevated creatine kinase when fasting, indicative of rhabdomyolysis. Metabolomics analysis identified elevated levels of a variety of acylcarnitine species in deficient mouse samples consistent with mild, global energy dysfunction. Most dramatically, animals develop a syndrome consistent with insulin insensitivity characteristic of type 2 diabetes mellitus in humans. A better understanding of the biochemical pathways and physiological role of ACAD10, as well as the pathophysiology of disorders occurring among this new ACAD family member will allow identification and treatment of patients with ACAD10 deficiency, as well as its role in obesity and type 2 diabetes.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Kormanik, Kaitlynknk14@pitt.eduKNK14
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairVockley, Gerardvockleyg@upmc.eduGEV1
Committee MemberMohsen, Al-WalidAl-Walid.Mohsen@chp.eduAAM27
Committee MemberKammerer, Candacecmk3@pitt.eduCMK3
Committee MemberUrban, Zsolturbanz@pitt.eduURBANZ
Date: 27 June 2014
Date Type: Publication
Defense Date: 17 April 2014
Approval Date: 27 June 2014
Submission Date: 2 April 2014
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 376
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Human Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: acyl-coa dehydrogenase 10, metabolism, T2D, beta-oxidation
Date Deposited: 27 Jun 2014 20:13
Last Modified: 01 May 2019 05:15
URI: http://d-scholarship.pitt.edu/id/eprint/20907

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