자료유형  

 학위논문

Control Number  

0016931340

International Standard Book Number  

9798379604639

Dewey Decimal Classification Number  

574

Main Entry-Personal Name  

Coraor Fried, Juliana.

Publication, Distribution, etc. (Imprint  

[S.l.] : Harvard University., 2023

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2023

Physical Description  

1 online resource(169 p.)

General Note  

Source: Dissertations Abstracts International, Volume: 84-12, Section: B.

General Note  

Advisor: Greka, Anna.

Dissertation Note  

Thesis (Ph.D.)--Harvard University, 2023.

Restrictions on Access Note  

This item must not be sold to any third party vendors.

Summary, Etc.  

요약Cellular vulnerability to free fatty acids (FFA) is implicated in the modern epidemic of obesity and its sequelae, including type 2 diabetes (T2D). However, studies to date have assumed that a few select FFAs are representative of broad structural categories, and currently there are no high-throughput, scalable approaches to characterizing the cellular effects of prolonged exposure to the diverse set of FFAs circulating in plasma. Furthermore, assessing how these FFA-mediated processes interact with genetic risk for disease remains elusive. Here we report the design and implementation of FALCON (a Fatty Acid Library for Comprehensive ONtologies) as an unbiased, multimodal interrogation of 61 structurally diverse FFAs across multiple cell types of interest. We identified a previously unrecognized subset of toxic monounsaturated fatty acids (MUFAs) that, at the cellular level, mimicked the effects of canonically harmful saturated fatty acids (SFAs) by altering ER stress, autophagy, insulin secretion, and inflammation. This subset of FFAs also induced a distinct lipidomic profile associated with decreased membrane fluidity. The integrated signature of a broader set of toxic FFAs, including toxic MUFAs, increased the sensitivity of detecting genes in a type 2 diabetes (T2D) genome-wide association study (GWAS) that could mediate both genetic and environmental risk. Among these loci, we further show that CMIP is a previously unrecognized regulator of cellular energy homeostasis. CMIP deficiency sensitizes multiple pancreatic beta cell models to FFA abundance and broader metabolic insult. This is due to metabolic inflexibility caused by dysregulation of Akt signaling. In sum, FALCON empowers the study of fundamental FFA biology and offers an integrative approach to identify much needed targets for diverse diseases associated with disordered FFA metabolism.

Subject Added Entry-Topical Term  

Cellular biology.

Subject Added Entry-Topical Term  

Biology.

Subject Added Entry-Topical Term  

Genetics.

Subject Added Entry-Topical Term  

Nutrition.

Index Term-Uncontrolled  

CMIP

Index Term-Uncontrolled  

FALCON

Index Term-Uncontrolled  

Fatty acid

Index Term-Uncontrolled  

Genome-wide association study

Index Term-Uncontrolled  

Lipotoxicity

Index Term-Uncontrolled  

Type 2 diabetes

Added Entry-Corporate Name  

Harvard University Biology Molecular and Cellular

Host Item Entry  

Dissertations Abstracts International. 84-12B.

Host Item Entry  

Dissertation Abstract International

Electronic Location and Access  

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Control Number  

joongbu:643348