Obesity and Hepatic Steatosis
NIH-funded project (DK072017)
Steatosis is the earliest and most prevalent stage of non-alcoholic fatty liver disease (NAFLD). Although steatosis generally has a benign outcome, some individuals develop progressive liver injury (steatohepatitis or NASH). An issue of primary importance to the understanding of NAFLD remains the study of the biochemical events that change the natural history of the disease from steatosis to NASH. A large majority of obese patients have hepatic steatosis and ~30% have NASH. This link is noteworthy, due both to the current obesity epidemic and the increased prevalence of liver damage in obese subjects. Disease progression in NAFLD is currently thought to be triggered by an acute insult or "second hit" that is superimposed on hepatic steatosis. However, the identity and nature of this "second hit" remains elusive. In this application, we demonstrate that the composition of fatty acids in the steatotic liver is variable in human obesity. Using dietary models of hepatic steatosis characterized by similar accumulation of total triglyceride but different compositions of fatty acids, we show that steatosis characterized by accumulation of saturated fatty acids leads to increased liver injury and reduced proliferative capacity. Preliminary data suggest that the link between accumulation of saturated fatty acids in the steatotic liver and liver cell injury involves ceramide and the selective upregulation of pro-apoptotic endoplasmic reticulum proteins. These data lead to the novel hypothesis that the composition of fatty acids in the steatotic liver is an important determinant of liver injury, and therefore may constitute an intrinsic "second hit". Therefore, the specific aim of this application is to elucidate how saturated fatty acids in the steatotic liver lead to increased liver cell injury. Studies will examine whether 1) de novo ceramide synthesis mediates saturated fatty acid induction of liver injury, 2) differences in fatty acid trafficking determine cytotoxicity, and 3) saturated fatty acids initiate liver cell injury through an endoplasmic reticulum localized apoptotic response.
Nutrient Effects on Insulin Action
NIH funded project (DK047416)
Organisms reprogram metabolic pathways to adapt to changes in nutrient availability, hormonal milieu and energy demands. This requires that stimuli are sensed and highly specific responses engaged. We propose that in the liver, the mitogen-activated protein kinase, c-Jun N-terminal kinase (JNK), links excessive nutrient metabolism with impaired insulin regulation of glucose production. The liver, by virtue of its anatomic position and selective regulatory features, buffers and is highly responsive to changes in nutrients. In particular sugars, such as sucrose and fructose, uniquely regulate and are selective metabolized by the liver. In the present application we show that chronic and acute sucrose ingestion, intraportal fructose infusion under controlled hyperglycemic conditions, and overexpression of hepatic glucokinase in vivo, and controlled fructose delivery in primary rat and human hepatocytes selectively increased hepatic JNK, the interaction of JNK with the scaffold protein, JIP1, and the interaction of JNK with insulin receptor substrate proteins. Normalization of the increased JNK activity improved insulin action and signaling. We propose that when hepatic sugar uptake exceeds requirements for glycogen and energy (hepatic sugar excess) the JNK signaling pathway is engaged as part of the adaptive response. Although a considerable amount of work has been done to establish the role of JNK as a mediator of insulin signaling, less is known about the mechanisms that link extracellular signals to the activation of JNK and the induction of insulin resistance in the liver. The aims of this proposal are to a) determine the cellular effectors of fructose-induced activation of JNK and insulin resistance and b) examine the role and regulation of the JNK signaling module in fructose-induced insulin resistance. The results from these studies will provide novel insight into nutrient regulation of signaling networks within the hepatocyte and to the etiology of metabolic diseases, such as obesity and type 2 diabetes, that have environmentally-based etiologies and are characterized by hepatic insulin resistance.
Plants as a source of bioactive molecules for the treatment of obesity and diabetes
Agriculture Experiment Station funded project
There are currently 150-175 million people worldwide who have diabetes. In the United States, 7% of the population has diabetes and an additional 15% can be classified as pre-diabetic. Despite the implementation of dietary and exercise intervention strategies, the presence of numerous educational programs and the development and use of multiple pharmacologic anti-diabetic drugs, the prevalence of diabetes, in particular type 2 diabetes, has continued to increase. In addition, populations with the most limited access to and trust in traditional health care (e.g. American and Alaskan Indians, Hispanics, African Americans) currently experience the highest prevalence of diabetes. Consequently, there is a growing need to develop novel approaches towards the management and prevention of diabetes. Worldwide, over 1200 species of plants have been recorded as traditional medicine for diabetes, however very few have been experimentally evaluated. In collaboration with Dr. Jorge Vivanco (Department of Horticulture and Landscape Architecture at CSU) we have screened 23 plant root exudates (secretions from the plant root) for insulin sensitizing and fat reducing properties. Preliminary data, provided later in the proposal, demonstrate that exudates from two plants, fenugreek and onion, enhance insulin action and/or reduce fat accumulation. The overall goal of this proposal is to develop an experimental paradigm that uses agricultural science as a tool to identify plant-based treatments for metabolic diseases. To develop such a paradigm this proposal will focus on onion, Allium cepae, and has the following specific aims:
- Evaluate the efficacy of onion root exudates as a potential early treatment for diabetes.
- Determine how onion root exudates enhance insulin action and reduce fat accumulation.
- Identify the bioactive compound(s) in plant root exudates from onion that enhance insulin action and reduce fat accumulation.