Date of Award
Spring 2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Molecular, Cellular, and Developmental Biology
First Advisor
Horsley, Valerie
Abstract
The skin is the largest organ in the human body and acts as a barrier between the inside and outside environments. A significant function of the skin is to maintain its structural integrity through extracellular matrix protein (ECM) homeostasis. Tissue fibrosis is characterized by a failure of ECM homeostasis, resulting in the accumulation of ECM proteins in healthy tissue. Systemic sclerosis is an autoimmune disease in which fibrosis develops throughout the body in organs such as the heart, lungs, and skin. Interestingly, during skin fibrosis, resident lipid-filled, mature adipocytes are depleted in humans and mice concomitant with ECM expansion. However, the mechanisms by which loss of lipid-filled adipocytes occurs during dermal fibrosis is not well understood. Here, we identify that adipocyte lipolysis via the rate-limiting enzyme, adipocyte triglyceride lipase (Atgl), is required for loss of adipose tissue during skin fibrosis in mice. We find that in both chemical and genetic mouse models, adipocyte lipolysis occurs early during skin fibrosis development and lipid storage is reestablished during fibrosis recovery. In mice lacking Atgl in adipocytes, maintenance of adipocyte lipid storage occurs in both chemical and genetic models of fibrosis development. Interestingly, loss of adipocyte Atgl-driven lipolysis results in precocious remodeling of the dermal ECM in mice as indicated by histological and transcriptional changes. These data suggest that adipocyte-derived fatty acids prevent ECM remodeling in fibroblasts during fibrosis development. Thus, adipocyte-derived fatty acids and their storage are a key component of fibrosis development and recovery and may be therapeutic for fibrotic diseases.
Recommended Citation
Caves, Elizabeth Ann, "Mechanisms and Functions of Lipodystrophy in Dermal Fibrosis" (2024). Yale Graduate School of Arts and Sciences Dissertations. 1454.
https://elischolar.library.yale.edu/gsas_dissertations/1454
