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Amany Alowaisi_PhD Thesis4.93 MB
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Dissertation
Mechanistic insights into the roles of Prohibitin 1 (PHB1) in metabolic homeostasis within the liver and circulation
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2025
DOI: 10.25820/etd.008199
Abstract
Metabolic homeostasis is fundamental for regulating whole-body energy balance and maintaining systemic health, and its disruption is involved in the pathogenesis of multiple chronic metabolic disorders, such as obesity, type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD). In addition, the consequences of metabolic dysregulation such as hyperglycemia and hepatic lipid accumulation not only drive progressive organ dysfunction but also increase the risk of cardiovascular disease, chronic kidney disease, and cancer. Despite advances in understanding the molecular mechanism that underlie metabolic dysfunction, the development of effective therapies remains limited, underscoring the critical need to identify new druggable targets that are involved in metabolic regulation.
Prohibitin-1 (PHB1) is an evolutionarily conserved protein from yeast to humans. It is involved in a broad spectrum of cellular functions, including proliferation, transcriptional control, signal transduction, and metabolic homeostasis. Aberrant expression or functional disruption of PHB1 have been associated with a variety of pathological conditions, such as chronic inflammation, immune dysregulation, tumorigenesis, neurodegenerative diseases, liver injury, and cardiovascular diseases. While intracellular PHB1 has been well characterized for its mitochondrial functions and been studied in various disease contexts, its metabolic functions remain incompletely understood. Importantly, early evidence reported altered hepatic PHB1 protein expression in mice models of hepatic steatosis and in obese humans at risk of metabolic dysfunction associated steatohepatitis (MASH), highlighting a potential role of PHB1 in maintaining hepatic metabolic homeostasis, however, the mechanisms are not completely understood. Furthermore, intracellular PHB1 has been implicated in insulin signaling and glucose metabolism, yet its extracellular systemic role in glucose metabolism has not been defined.
In this work, we investigated the functions of both hepatic and circulating PHB1 (i.e. in blood) in metabolic regulation. First, we used hepatocyte-specific PHB1 deficient (hPHB1-KD) mice to determine the role of PHB1 in hepatic metabolic homeostasis. In hPHB1-KD mice, we observed hepatic steatosis, impaired glucose clearance and reduced insulin sensitivity. Mechanistically, these alterations were associated with dysregulation of a central regulator of cell metabolism, the mechanistic target of rapamycin complex1 (mTORC1) signaling pathway, underscoring PHB1’s role in maintaining hepatic metabolic homeostasis. Of Note, the metabolic consequences of hepatic PHB1 deficiency were sex specific as male mice developed steatosis and insulin resistance, whereas females were protected. This protection may relate to the previously reported interaction of PHB1 with estradiol, known for its favorable metabolic effects in liver, and suggests sex-dependent regulation of PHB1 function.
Beyond the liver, we provide the first evidence that circulating PHB1 acts as a regulator of systemic glycemic control. Plasma PHB1 levels were reduced in obese, insulin-resistant mice but increased acutely following dextrose administration, indicating dynamic responsiveness to nutritional state. In addition, administration of recombinant PHB1 (rPHB1) enhanced glucose uptake in C2C12 myotubes independently of insulin and synergistically with insulin. Furthermore, rPHB1 treatment lowered basal blood glucose and improved insulin sensitivity during hyperinsulinemic–euglycemic clamp studies in mice and promoted tissue-specific glucose uptake in skeletal muscles and heart without altering plasma insulin levels. These findings suggest that PHB1 facilitates systemic glucose clearance through both insulin-independent and insulin-sensitizing mechanisms.
Collectively, our research findings establish PHB1 as a critical regulator of hepatic lipid metabolism and systemic glycemic control. By integrating intracellular and extracellular functions of PHB1, this work expands our understanding of PHB1 metabolic functions and identifies it as a potential therapeutic target for MASLD, insulin resistance, and related metabolic diseases.
Details
- Title: Subtitle
- Mechanistic insights into the roles of Prohibitin 1 (PHB1) in metabolic homeostasis within the liver and circulation
- Creators
- Amany Ali Ahmad Alowaisi
- Contributors
- Ethan Anderson (Advisor)David Roman (Committee Member)Marie Gaine (Committee Member)Reza Nejad Nik (Committee Member)Vitor Lira (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Pharmacy (Clinical Pharmaceutical Sciences)
- Date degree season
- Autumn 2025
- DOI
- 10.25820/etd.008199
- Publisher
- University of Iowa
- Number of pages
- xxi, 124 pages
- Copyright
- Copyright 2025 Amany Ali Ahmad Alowaisi
- Language
- English
- Date submitted
- 11/12/2025
- Description illustrations
- illustrations, tables, graphs
- Description bibliographic
- Includes bibliographical references (pages 115-124).
- Public Abstract (ETD)
- To maintain health, the human body depends on tightly regulated mechanisms that ensure a balanced supply and utilization of energy and nutrients, a state known as metabolic balance. When this balance is disrupted, it can lead to serious diseases such as obesity, fatty liver disease, and type 2 diabetes. These conditions often bring long-term complications, including heart disease, kidney problems, and even cancer. Although progress has been made in understanding the causes of abnormal metabolic processes, effective treatments are still limited. This makes it essential to discover new factors that help control metabolism.
In this research, we studied a protein called prohibitin-1 (PHB1), that is present inside and outside our cells and is known to support cell functions in multiple ways. However, its role in regulating metabolism has not been fully understood.
We found that PHB1 in the liver is essential for keeping fat metabolism in balance. Depleting PHB1 from liver cells in mice caused fatty liver and disrupted blood sugar control, in males. The female mice were protected, possibly because of having the sex hormone estrogen; however, this hypothesis warrants further study.
We also identified, for the first time, that PHB1 in the blood helps to regulate glucose level. In obese mice, PHB1 levels in blood were reduced. In addition, administering PHB1 to healthy mice lowered blood glucose, and boosted insulin sensitivity, particularly in muscles and the heart.
Together, these findings show that PHB1 is a key player in controlling both fat and glucose metabolism. Targeting PHB1 may be promising for treating diabetes, fatty liver disease, and other metabolic disorders.
- Academic Unit
- Pharmacy
- Record Identifier
- 9985135048302771
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