Current Projects

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Role of Exercise on the Mitigation of Liver Fibrosis

Non-alcoholic hepatic cirrhosis is a dysfunction in hepatic fibrogenesis that involves an imbalance between hepatic autophagy and extracellular matrix formation. Hepatic fibrogenesis is intrinsically regulated by the transforming growth factor-beta (TGF-beta) signaling pathway. During NASH, it is hypothesized that excessive lipid accumulation paired with chronic low-grade inflammation and immune cell activity promotes an increased activity of the TGF-beta signaling pathway. The TGF-beta cytokine is multi-functional, with a well described role in the regulation of hepatic fibrosis and regeneration (Mallat et al., 2013; Thenappan et al., 2010). When activated by proteolytic cleavage by matrix metalloproteases, TGF-beta binds to TGF-beta receptor 2 followed by dimerization (i.e., binding) with TGF-beta receptor 1 leading to phosphorylation and activation of TGF-beta signaling pathway (Onichtchouk et al., 1999).  


In our lab, we have recently discovered that voluntary wheel running during weight-loss increases the expression of BAMBI, bone morphogenetic protein activin membrane inhibitor. BAMBI acts as a pseudo-TGF-beta receptor 2 and when present, TGF-beta binds to BAMBI and subsequent dimerization to TGF-beta receptor 1 leads to inhibition of the TGF-beta signaling pathway (Onichtchouk et al., 1999). Based on our initial evaluations, it remains unclear if the increased expression of BAMBI downregulates the activity of TGF-beta signaling and histological signs of fibrosis. Furthermore, it remains unclear mechanistically how exercise may increase BAMBI. 


The aim of this study will be to determine if voluntary wheel running (i.e., physical activity) reduces the development of fibrosis during the consumption of a Western diet. The results from this study will be used to advance our understanding of non-alcoholic cirrhosis, as well as the use of physical activity as a therapeutic intervention for the prevention and treatment of NASH and related pathologies.


Dietary Impact on Blood Brain Barrier Tight Junctions (R21-K. Witt) 

In collaboration with Ken Witt (PI) and Karin Sandoval in the Department of Pharmaceutacal Sciences, we are evaluating the effects of prolong consumption of a diet high in omega-3 fatty acids (fish oils) on both BBB tight junctions, as well as hepatic factors that may mediate the development of neurodegenerative diseases. Below is the project abstract.


A critical property of the blood-brain barrier (BBB) is the unique complex of tight junctions (TJs) that exists between adjacent endothelial cells, which impede paracellular diffusion and help maintain brain homeostasis.  Numerous lines of evidence implicate BBB TJ dysfunction as a primary contributor to central nervous system (CNS) disease. While it has become increasingly evident that pro-inflammatory high-fat “Western” diets contribute to CNS disease, the impact of such diets on the BBB TJs has not been fully evaluated.  Likewise, the potentially beneficial impact of omega-3 (ω3) polyunsaturated fatty acids (PUFAs) on BBB TJs also remains unclear.  The connections between dietary fats and actions of the peroxisome proliferator-activated receptor-γ (PPARγ) also have significant implications to BBB TJ regulation and CNS disease.  PPARγ activation has been identified with enhancement of BBB integrity, with actions linked to dietary fats, as primary ω-3 PUFAs are natural PPARγ ligands.  The goal of this examination is to evaluate the impact of diet and PPARγ agonist action on BBB TJ integrity and protein regulation, respective to acute inflammatory response.  This study is divided into two aims: 1) Determine the effect of Western vs. ω-3 based diets on BBB TJ integrity and protein regulation against an inflammatory challenge.   Evaluations include a lipopolysaccharide (LPS) inflammatory challenge to delineate susceptible and response to inflammation.  2) Determine the effect of PPARγ agonist treatment on BBB TJ integrity and protein regulation against a Western-based diet and LPS inflammatory challenge.  Evaluations will be conducted in C57BL/6 mice using established methodology.  This exploratory study will provide novel insight into the impact of dietary fats and PPARγ agonist actions on the health and resilience of the BBB TJs, as well as a greater understanding of inflammatory influences.  Additionally, it will serve as the foundation for future examinations respective to BBB regulation and disease outcomes.


Weight-Cycling Project

In an attempt to lose weight, too often people experience repeated cycles of weight loss followed by weight regain when the diet strategy is interrupted (often called weight-cycling or yo-yo dieting). The topic of weight-cycling and its health-related consequences, such as obesity, cancer, type 2 diabetes mellitus, and hypertension have been the source of considerable controversy. Several large population based prospective studies clearly illustrate an association between weight-cycling and an increased risk for all-cause and cardiovascular mortality, whereas others have not shown a change in risk. The link between weight-cycling and increased cardiovascular mortality are not well understood; however, enhanced weight regain, alterations in the composition and quantities of tissue lipids, impaired insulin signaling, and elevated plasma triglyceride levels have been observed in both human and animal models of weight-cycling. 


The use of physical activity is a common strategy for the prevention of obesity and to improve the efficacy of weight reduction. Interestingly, when weight reduction interventions that incorporate physical activity have been interrupted, the amount of weight-regained has been inconsistent. This can be attributed to the various volumes and intensities of physical activity performed in these observational studies. The consequences of weight regain with and without physical activity on nonalcholic fatty liver disease (NAFLD) remains unknown. The specific aims for the current project being conducted in the Exercise Biochemistry and Physiology Laboratory are to 1) define how weight-cycling (the cycle of weight-loss followed by subsequent weight regain) effects the development of NAFLD and 2) to determine if physical activity during weight-cycling provides protection beyond what is observed during “diet-only” induced weight-loss and also during subsequent weight regain. It is hypothesized that 1) weight-cycling will cause a more advanced state of NAFLD and 2) physical activity will prove to be a powerful non-pharmacological strategy for the treatment of NAFLD, providing protection during subsequent weight regain. Nonalcholic fatty liver disease is characterized by 1) insulin resistance, 2) enhanced inflammatory state,  and 3) excessive lipid storage (lipotoxicity). The therapeutic role of physical activity on these three key factors in the pathogenesis of NAFLD during weight-cycling will be evaluated in this investigation.