Obesity-linked diseases are the focus of research in the Greene Laboratory at Auburn University. In particular, the laboratory is interested in: 1) the development and progression of fatty liver disease and 2) the molecular link between obesity and certain forms of cancer.
An overview of research in the laboratory can viewed in an excerpt from a presentation given the Auburn University Research Advisory Board. The full presentation can be found on the Research Advisory Board website in the video titled "Nutrition: The emperor of health and maladies that afflict us all". If your media player can not open the video, you need to download a codec from GoToMeeting.
The public health consequences of the obesity epidemic in the United States and Alabama in particular are truly staggering: increased risk of developing cardiovascular disease, certain forms of cancer, and type 2 diabetes (Guh et al, 2009). The most recent estimates for the state of Alabama suggest that obesity will rise to greater than 60% by 2030 (Trust For America’s Health, 2012). Nationally, it has been estimated – if obesity rates continue to climb - that the number of new diagnoses for cardiovascular disease, certain forms of cancer, and type 2 diabetes could increase 10 times in the next ten years (Trust For America’s Health, 2012).
Nonalcoholic fatty liver disease (NAFLD) is a clinico-histopathological entity with histological features that ranges from fat accumulation in hepatocytes without concomitant inflammation or fibrosis (simple hepatic steatosis) to hepatic steatosis with a necroinflammatory component (steatohepatitis) that may or may not have associated fibrosis. The latter condition, referred to as nonalcoholic steatohepatitis (NASH), may progress to cirrhosis in up to 20 percent of patients. (View Natural History here)
Although the pathogenesis of NAFLD is still unclear, insulin resistance is widely thought to be the main mechanism leading to hepatic steatosis, and perhaps also to hepatic steatohepatitis. Genetic susceptibility plays a role in the occurrence of NAFLD. However, population gene pools shift quite slowly. The current increase in these disorders may reflect changes in environmental factors, especially diet.
The exact etiology for transformation of steatosis to NASH remains obscure; however, a classical “two-hit” hypothesis has been proposed to explain progression (Day and James, 1998). Steatosis constitutes the “first hit.” Proinflammatory cytokines (e.g. tumor necrosis factor-alpha), oxidative stress, and lipid peroxidation constitute the “second hit” leading to NASH (Jou et al, 2008). Recently an alternative “non triglyceride lipotoxicity” hypothesis has been put forward implicating metabolites of free fatty acids in hepatocyte injury and development of NASH (Neuschwander-Tetri, 2010).
The classical (alpha, beta, and gamma), and novel (delta, epsilon, and theta) protein kinase C (PKC) isoforms constitute a set of intracellular signaling molecules that are activated by lipids. In fact, the novel PKC isoforms have the highest affinity of all the PKC isoforms to bind diacylglycerol, a free fatty acid metabolite (Giorgione et al 2006). Our in vitro studies using cells of hepatic origin show that PKC delta (PKCδ) regulates cellular insulin resistance (Greene et al, 2004; Greene et al, 2006; Greene et al, 2010a), which suggests that PKCδ has the potential to be a good target for therapeutics to treat insulin resistance
Our recent studies in methionine and choline deficient (MCD) diet fed mice, which develop hepatic steatosis, inflammation, apoptosis, and fibrosis histologically similar to human NASH (Anstee and Goldon, 2006; Kirsch et al, 2003), demonstrated that PKCδ protein expression and activation are elevated in the liver of mice fed the MCD diet compared to a control diet (Greene et al, 2010b). Further, we observed in a cellular model of NASH that PKCδ knockdown blocked JNK activation and blunted palmitate-induced apoptosis (Greene et al, 2010a).
Two of the most prevalent diseases in modern society are obesity and cancer, yet these two diseases are generally thought of separately, when in fact there is strong epidemiological and experimental evidence to link the two. The increased risk of cancer associated with obesity has been well documented in the following cancer types: Breast (after menopause), Colon and rectum, Endometrium (lining of the uterus), Esophagus, Gallbladder, Kidney, Pancreas, and Thyroid. With up to 20% of all cancer deaths in the Unites States believed to be attributed to obesity, we are faced with a serious public health problem destined to worsen over time. Consequently, a detailed understanding of the biological mechanisms underlying the link between obesity and cancer is urgently needed. Moreover, there is a need for new animal models of obesity and human cancer for pre-clinical evaluation of therapeutics. Our approach is to 1) develop novel animal models of obesity and cancer to determine the role of obesity in human cancer and 2) use the unique animal models as preclinical models to evaluate human cancer and obesity/diabetes therapeutics.