Author ORCID Identifier

https://orcid.org/0000-0001-5258-8318

Date Available

12-14-2024

Year of Publication

2024

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Medicine

Department/School/Program

Pharmacology and Nutritional Sciences

Advisor

Dr. Terry D. Hinds, Jr.

Abstract

Insulin resistance and metabolic dysfunction-associated steatotic liver disease (MASLD) have become significant health issues worldwide. Increased prevalence of hepatic insulin resistance and MASLD worsens the threat of its progressive complications, such as liver fibrosis, which can lead to cirrhosis and death if left untreated. Treatments for MASLD-induced liver fibrosis are mainly insulin sensitizers. However, activating insulin signaling leads to a higher death rate in end-stage liver fibrosis. This dissertation discusses the emerging insights into hepatic insulin resistance and potential treatment targets in the heme degradation pathway for reversal. We also investigated the mechanisms that the insulin receptor (INSR) regulates in hepatic stellate cell (HSC) function in response to insulin and profibrogenic stimulation transforming growth factor beta (TGFβ). We mutated the intact INSR to be partially responsive in human HSCs and treated them with insulin or TGFβ. We found that insulin-INSR signaling regulated HSC cell growth and movement, essential for developing liver fibrosis. The insulin-INSR signaling also regulates HSC’s transcriptional responsiveness and altered protein-tyrosine kinase (PTK) and serine-threonine kinase (STK) activity in response to TGFβ stimulation. These findings contribute to possibly developing safer treatments for liver diseases, which have been predicted to have complicated over one billion people worldwide.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2024.460

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