Access Type

Open Access Dissertation

Date of Award

January 2020

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Pathology

First Advisor

Todd Leff

Second Advisor

Jian Wang

Abstract

The amino acid glycine is involved in generation of multiple critical metabolites including glutathione, heme, and creatinine. Interestingly, in both humans and rodents, circulating glycine levels are significantly reduced in obesity, glucose intolerance, type II diabetes and non-alcoholic fatty liver disease. The glycine cleavage system is the predominant glycine degradation pathway in humans. The rate-limiting enzyme of glycine cleavage system is glycine decarboxylase (GLDC), and loss-of-function mutations of GLDC cause hyperglycinemia. Here, we show that GLDC gene expression is upregulated in livers of mouse models of diabetes and diet-induced obesity as well as in the fasted state in normal animals. In exploring the hormonal signals that mediate these regulatory events we found that both glucagon and insulin stimulated GLDC gene expression. In primary rat hepatocytes, GLDC expression was strongly stimulated by glucagon and cAMP, and mildly with insulin while in a rat hepatoma cell line, insulin strongly stimulated GLDC expression as compared to cAMP. We identified both cAMP-response element binding protein 1 (CREB1) and activating transcription factor 1 (ATF1) as mediators of the glucagon regulation, while insulin responsive transcription factor sterol regulatory element binding protein 1c (SREBP1c) mediated the insulin stimulatory effect on GLDC transcription. We also observed that altering GLDC expression levels strongly affected intracellular glutathione levels and levels of reactive oxygen species (ROS). Our findings suggest that the hormonal regulation of GLDC may contribute to a compensatory increase in glutathione production as a defense against metabolic disease-associated oxidative stress.

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