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From sugar to acetate - the origins of acetyl-CoA dictate its use in cells and in mice / Steven Zhao.
Connect to full text Available online
View online- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Zhao, Steven, author.
- Language:
- English
- Subjects (All):
- Molecular biology.
- Biochemistry.
- Biology.
- Cellular biology.
- Cell and molecular biology--Penn dissertations.
- Penn dissertations--Cell and molecular biology.
- Local Subjects:
- Molecular biology.
- Biochemistry.
- Biology.
- Cellular biology.
- Cell and molecular biology--Penn dissertations.
- Penn dissertations--Cell and molecular biology.
- Genre:
- Academic theses.
- Physical Description:
- 1 online resource (197 pages)
- Contained In:
- Dissertations Abstracts International 81-08B.
- Place of Publication:
- [Philadelphia, Pennsylvania] : University of Pennsylvania ; Ann Arbor : ProQuest Dissertations & Theses, 2019.
- Language Note:
- English
- System Details:
- Mode of access: World Wide Web.
- text file
- Summary:
- Changes in environmental factors, diet, and genetics all influence metabolism, which is frequently dysregulated at the cellular and organismal levels in diseases such as metabolic syndrome, cancer, and inborn errors of metabolism. These maladies are often intertwined; for example, metabolic diseases such as obesity and inborn errors of metabolism such as fumarate hydratase deficiency can both increase the risk for developing certain cancers. One metabolic pathway frequently altered in disease is de novo lipogenesis (DNL). Aberrant DNL is believed to play a critical role in pathogenesis of cancer and non-alcoholic fatty liver disease (NAFLD), a manifestation of metabolic syndrome in the liver. DNL requires the metabolite, acetyl-CoA, which is predominantly synthesized in the cytosol and nucleus from the cleavage of citrate through the action of ATP-citrate lyase (ACLY). Consistent with its role in DNL, elevated levels or activity of ACLY is frequently observed in cancer and NAFLD. Therefore, I utilized a genetic loss-of-function approach coupled with metabolomic methods to investigate how abrogating ACLY impacts metabolism in proliferating cells and the liver. Unexpectedly, impairment of ACLY leads to metabolic compensation through ACSS2-dependent acetate usage at the cellular and tissue levels. Moreover, by depleting ACLY, we identify a link between dietary carbohydrate and microbiome-derived acetate in supporting hepatic DNL. These findings have revised our understanding of acetyl-CoA metabolism in cells, and how nutritional sources feed into this pathway in disease contexts.
- Notes:
- Source: Dissertations Abstracts International, Volume: 81-08, Section: B.
- Includes supplementary digital materials.
- Advisors: Wellen, Kathryn E.; Busino, Luca; Committee members: Zoltan Arany; Terence Gade; Aalim Weljie.
- Department: Cell and Molecular Biology.
- Ph.D. University of Pennsylvania 2019.
- Local Notes:
- School code: 0175
- ISBN:
- 9781392528594
- Access Restriction:
- Restricted for use by site license.
- This item is not available from ProQuest Dissertations & Theses.
- This item must not be sold to any third party vendors.
- This item must not be added to any third party search indexes.
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