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Understanding the Role of Acetyl-CoA Synthesis in Hepatic Lipid Homeostasis / Joyce Y Liu.
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Liu, Joyce Y., author.
- Language:
- English
- Subjects (All):
- Biochemistry.
- Pharmacology.
- Molecular biology.
- Genetics.
- Biochemistry and Molecular Biophysics--Penn dissertations.
- Penn dissertations--Biochemistry and Molecular Biophysics.
- Local Subjects:
- Biochemistry.
- Pharmacology.
- Molecular biology.
- Genetics.
- Biochemistry and Molecular Biophysics--Penn dissertations.
- Penn dissertations--Biochemistry and Molecular Biophysics.
- Physical Description:
- 1 online resource (93 pages)
- Distribution:
- Ann Arbor : ProQuest Dissertations & Theses, 2023
- Contained In:
- Dissertations Abstracts International 85-08B.
- Place of Publication:
- [Philadelphia, Pennsylvania] : University of Pennsylvania, 2022.
- Language Note:
- English
- Summary:
- Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive hepatic lipid accumulation and its pathogenesis involves dysregulated lipid homeostasis, including elevated de novo lipogenesis (DNL). ATP citrate lyase (ACLY) synthesizes acetyl-CoA, the requisite two-carbon precursor for DNL, and thus, has emerged as a target of interest for NAFLD, which currently lacks approved pharmacological treatments. The FDA-approved LDL-cholesterol lowering drug bempedoic acid (BPA) inhibits hepatic ACLY and reduces steatosis in mice. However, prior work in genetic models suggests that targeting of ACLY to prevent hepatic lipid accumulation may only be effective in certain contexts, in part due to compensation by the alternative acetyl-CoA producing enzyme, acetyl-CoA synthetase 2 (ACSS2). In this work, we aimed to investigate the role of acetyl-CoA production in the development of diet-induced steatosis and to assess its suitability as a therapeutic target. Using a combination of in vivo genetic models of ACLY and ACSS2 deficiency, dietary manipulations, and treatment of ACLY knockout mice with BPA, we found that loss of ACLY counterintuitively exacerbated hepatic lipid accumulation on a Western Diet. These effects were independent of compensation by ACSS2, as simultaneous knockout of ACLY and ACSS2 did not rescue the worsened steatosis. We further observed that BPA exerted its effects on reducing lipid accumulation in an ACLY-independent manner and, in contrast to ACLY loss, promoted PPARα activation. Overall, the data demonstrate a previously unappreciated role for ACLY in restraining hepatic lipid accumulation and support the potential use of BPA for NAFLD/NASH treatment, highlighting the importance of further defining its mechanistic targets in this setting.
- Notes:
- Source: Dissertations Abstracts International, Volume: 85-08, Section: B.
- Advisors: Wellen, Kathryn E.; Baur, Joseph A.; Sharp, Kim A.; Committee members: Brady, Donita C.; Arany, Zoltan P.; Snyder, Nathaniel W.
- Department: Biochemistry and Molecular Biophysics.
- Ph.D. University of Pennsylvania 2023.
- Local Notes:
- School code: 0175
- ISBN:
- 9798381509762
- Access Restriction:
- Restricted for use by site license.
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