Master of Science in Molecular Pathology and Immunology
Graduate School of Biomedical Sciences
School of Osteopathic Medicine
Genesis Biotechnology Group
Salvatore Caradonna, PhD
Committee Member 1
Scott Gygax, PhD
Committee Member 2
Joseph Nickels, PhD
Metabolic Syndrome, Non-alcoholic Fatty Liver Disease, Mice, Lipolysis, Liver, Metabolic Diseases, Fatty Acid Transport Proteins, Transcription Factor CHOP
Metabolic syndrome (MetS) is a term used to define a set of metabolic diseases: obesity, type 2 diabetes (T2D), hyperlipidemia, hypertension, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic hepatosteatosis (NASH). Those with MetS have a higher incidence of cardiovascular disease and stroke. Current drug treatments for MetS treat the individual pathologies associated with the diseases, rather than directly targeting MetS as a whole. We hypothesize that the inhibition of a ubiquitous lipid transporter known as ARV1 can improve pathologies associated with MetS. To test this hypothesis, we utilized liver tissue from mARV1 knockout mice fed a high-fat diet and examined whether loss of mARV1 results in a reduction in unfolded protein response signaling (UPR), a stress-activated pathway that precedes the chronic inflammation associated with NASH. During activation of this pathway, phosphorylation of the UPR kinase sensor, IRE1α, activates the transcription of genes involved in stress, including the gene, CHOP. Here, we found that loss of mARV1 caused a reduction in liver IRE1α phosphorylation but did not abolish CHOP transcription. These findings suggest that ARV1 inhibition activates certain branches of the UPR in a noncanonical manner. Interestingly, CHOP activation correlated with a decrease in serum triglycerides, an increase in high-density lipoprotein, and an increase in non-esterified free fatty acids in high fat-fed mARV1 knockout mice. Overall, our data strongly suggest that mARV1- knockout animals may be resistant to the initiation of hepatic apoptosis and NASH under high fat conditions and may undergo accelerated lipolysis when compared to wild-type animals.
Mitchell, Shad Anthony, "Loss of mARV1 Promotes CHOP Signaling in Mouse Liver" (2018). Graduate School of Biomedical Sciences Theses and Dissertations. 32.