Collaborate 2 Cure
August 21, 2017

Enterprise Center of Johnson County (ECJC)
4220 Shawnee Mission Parkway, Suite 350B, Fairway, KS 66205

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A Novel Preclinical Model for Obesity-Linked NASH and HCC

Obesity increases the risk for non-alcoholic steatohepatitis (NASH) and hepatocarcinogenesis. In addition, sex differences are known to exist in their incidence rates, which is higher in males. However, the underlying mechanisms involved in the disease process and in sex differences in their incidence remain unclear. There is an urgent need to better understand the underlying mechanisms involved in obesity-linked NASH and HCC development because of the continuous increase in their incidence worldwide. The major obstacles in the mechanistic study are the lack of suitable animal models that spontaneously develop obesity-linked NASH and HCC in a progressive manner and difficulty associated with the study of disease onset in humans. Moreover, a suitable animal model is required for appropriate and meaningful intervention and preclinical studies. Recently, we have developed a transgenic obese mouse model (Mito-Ob) by prohibitin mediated mitochondrial remodeling in adipocytes. The Mito-Ob mice develop obesity in a sex-neutral manner, but obesity-associated adipose inflammation and metabolic dysregulation in male sex-specific manner. With aging, the male Mito-Ob mice spontaneously develop NASH and HCC. In contrast, the female Mito-Ob mice maintained normal glucose and insulin levels and did not develop NASH and HCC. Thus, Mito-Ob mice provide a proof-of-concept that obesity-associated metabolic and immune dysregulation indeed have a central role in the pathogenesis of NASH and HCC. Furthermore, the Mito-Ob mice provide a new paradigm in sex differences in HCC incidence, and revealed a sex-dimorphic role of prohibitin in adipose and immune functions. Thus, the Mito-Ob mice have created an opportunity to advance our understanding of obesity-linked NASH and HCC including sex differences in their prevalence.

Speaker- Suresh Mishra, MSc, PhD

Dr. Mishra received his M.Sc. and Ph.D. in biochemistry and endocrinology from Delhi University, Delhi, India. Subsequently, he received his post-doctoral training with Prof. C.V. Rao at the University of Louisville and with Prof. Liam Murphy at the University of Manitoba, Canada. Currently, he is an Associate Professor in the Department of Internal Medicine at the University of Manitoba, Canada. His current research uses the transgenic mouse models to understand adipose-immune crosstalk with special interest in obesity-linked diabetes and cancer. In particular, he is interested in the role and regulation of an evolutionarily conserved mitochondrial protein, prohibitin, in sex differences adipose and immune functions and in immunometabolism. 

Potential Role for SPECC1L Cytoskeletal Protein in Membrane Dynamics

Orofacial clefts (OFCs) are common anomalies that occur in 1/700 live births. Mutations in SPECC1L, a novel cytoskeletal protein, have been identified in patients with severe atypical and syndromic OFCs. We previously demonstrated that SPECC1L deficiency results in reduced PI3K-AKT signaling and increased expression of adherens junction components in vitro in U2OS osteosarcoma cells, and in vivoin Specc1l mutant embryos. Furthermore, SPECC1L-knockdown (kd) 293T embryonic kidney cells lose their ability to adhere to extracellular matrix (ECM) upon high confluency.  We now show that this ECM adhesion defect is also accompanied by increased cell-cell adhesion and reduced pan-AKT levels. SPECC1L-kd cells form more spheroids than wildtype cells. Upregulation of the AKT pathway with the AKT activator SC-79 delayed loss of ECM adhesion, indicating a causal relationship. SPECC1L-kd cells also displayed decreased intracellular pH compared to wildtype cells. Staining with Acridine Orange revealed an increase in the number of acidic organelles in SPECC1L-kd cells, especially at high density. Western blot analysis confirmed drastic upregulation of lysosomal marker LAMP1 in SPECC1L-kd cells at high density. Mitochondrial function is also altered in SPECC1L-kd cells. Both basal and maximal respiration are increased and proton leak is reduced, indicative of increased ATP demand in the cell. This increased demand for ATP is consistent with the possibility of increased depolarization of the plasma membrane due to partial permeabilization caused by unregulated endocytic activity. Thus, our data support a novel role for SPECC1L in membrane dynamics affecting cell adhesion, endocytosis, and respiration through regulation of AKT signaling.

Speaker: Irfan Saadi, PhD

Irfan Saadi, PhD, is an Associate Professor in the Department of Anatomy and Cell Biology at the University of Kansas Medical Center (KUMC), in Kansas City, KS. He is also a member of the Kansas Intellectual and Developmental Disabilities Research Center and the Institute of Reproductive Health and Regenerative Medicine. Dr. Saadi received his PhD in Genetics (2003) from The University of Iowa.  He did his postdoctoral training in the area of Developmental Genetics at Harvard Medical School and The Forsyth Institute. Over the past 20 years, Dr. Saadi’s research has focused on identification and analysis of disease-causing mechanisms. The long-term goal of his lab is to understand the etiology of complex craniofacial disorders affecting face, palate, and tooth. Currently, he is following-up on his identification of the first mutations in a novel cytoskeletal gene, SPECC1L, in patients with facial clefts. Understanding the function of novel genes, such as SPECC1L, promises to elucidate many fundamental mechanisms that underlie embryonic development and malformations.