Cardiometabolic Disease Prevention

cardiovascular and metabolic diseases

The work performed in the laboratories of the Cardiometabolic Disease Prevention program is aimed at a better understanding of the molecular and cellular mechanisms of cardiovascular disease (primarily heart disease, stroke, and hypertension), metabolic syndrome, fatty liver disease, and type 2 diabetes. The role of oxidative stress and inflammation in the causation of these diseases is being investigated, as well as the protective effects of micronutrients and other dietary factors or supplements, such as vitamins C and E, lipoic acid, omega-3 fatty acids, and flavonoids.

Faculty Involved: Balz Frei, Ph.D., Donald B. Jump, Ph.D., Fred Stevens, Ph.D., and Maret G. Traber, Ph.D.

Metabolism of Dietary and Endogenous Fats

Principal Investigator: Donald B. Jump, Ph.D.

The type and quantity of dietary fat ingested affects human health, particularly the onset and progression of chronic diseases like diabetes, obesity, metabolic syndrome, and atherosclerosis. The liver plays a central role in whole-body carbohydrate and lipid metabolism. Our research focuses on defining mechanisms for fatty acid regulation of hepatic carbohydrate and lipid metabolism.

Our research has assessed the role hepatic fatty acid synthesis plays in the control of complications linked to type 2 diabetes mellitus (T2DM) and obesity, particularly hyperglycemia and fatty liver disease. Hepatic lipid synthesis, including the synthesis of saturated and mono- and polyunsaturated fatty acids, is significantly altered in humans with T2DM, obesity, and metabolic syndrome. Our studies have identified a novel connection between enzymes involved in monounsaturated and polyunsaturated fatty acid synthesis and the control of hepatic glucose production and liver fat content. While these studies clarify molecular interactions between different metabolic pathways, they may also identify possible novel approaches to control certain diabetic complications.

Other research in my laboratory has assessed the capacity of dietary omega-3 fatty acid supplementation to control high-fat, diet-induced, non-alcoholic fatty liver disease (NAFLD). The incidence of NAFLD closely parallels the incidence of obesity in the U.S. population. NAFLD is a spectrum of diseases that span simple fatty liver (benign steatosis) to non-alcoholic steatohepatitis (NASH). NASH is characterized as fatty liver with inflammation, fibrosis, oxidative stress, and hepatic damage. If left unchecked, NASH can progress to cirrhosis and liver cancer. Our recent studies have established that dietary omega-3 fatty acids found in fish oil (eicosapentaenoic acid and docosahexaenoic acid) can be used at clinically relevant levels of intake to attenuate multiple markers of NASH (hepatosteatosis, inflammation, and fibrosis) in a mouse model of high-fat, diet-induced NASH. Future studies will determine whether specific omega-3 fatty acids, either alone or in combination with other treatments, can be used in therapy to reduce hepatic damage associated with obesity-linked NASH.

Role of Lipoic Acid in Vascular Inflammation and Atherosclerosis

Principal Investigator: Weijian Zhang, Ph.D.

Compelling evidence links oxidative stress and inflammation to major cardiovascular disease (CVD), including atherosclerosis, hypertension, coronary heart disease, and stroke. While antioxidants and anti-inflammatories have been found to inhibit atherosclerosis in experimental animals, antioxidant vitamin trials to prevent or slow CVD in humans have been disappointing. The disparity between clinical trials and animal studies points to major gaps in our understanding of the effects and mechanisms of antioxidants in atherosclerotic vascular diseases in humans. Our long-term goal is to target oxidative stress and inflammation in humans to better understand their etiologic roles in atherosclerosis. The intracellular redox environment regulates endothelial cell function; an imbalance in this redox environment may cause upregulation of cellular adhesion molecules and pro-inflammatory and prothrombotic mediators, all of which promote atherosclerosis. We have found that lipoic acid affects redox-sensitive cell-signaling processes, transcription factors, and gene expression in endothelial and mononuclear cells, and exerts strong anti-inflammatory and anti-atherogenic effects in experimental animals. In collaboration with researchers at Oregon Health & Science University, we are currently testing whether lipoic acid supplementation reduces risk factors for the development of atherosclerosis in humans by attenuating oxidative stress and inflammation.

Vitamin C, Lipid Peroxidation, and Oxidative Stress

Principal Investigator: Fred Stevens, Ph.D.

The research mission of the Stevens lab is to determine the role of phytochemicals and vitamins in preventing or treating cardiovascular and metabolic diseases. We develop analytical methods for targeted and untargeted metabolomics experiments to determine the biological effects of phytochemicals and vitamins in supplementation/deficiency studies using cell culture, animal models, and humans. Our lab has developed novel biomarkers to examine the role of oxidative stress and the protective effects of dietary supplements in human health and disease.

Vitamin C and oxidative stress

This research project aims to determine how vitamin C interacts with lipid peroxidation products and how vitamin C prevents cellular damage to proteins caused by oxidized lipids. We are interested in these interactions because lipid peroxidation contributes to the development and progression of chronic inflammatory and age-related diseases, such as atherosclerosis. The tools that we use for our research include liquid chromatography coupled to mass spectrometry (LC-MS/MS) for analysis of lipid conjugates in complex biological matrices, synthesis of (labeled) lipids and their conjugates, cell culture for investigating the biological properties of oxidized lipids and their conjugates, and animal models for studying the in vivo formation, metabolism, and excretion of oxidized lipids. One of our main findings is that vitamin C, at physiologically relevant concentrations, prevents adduct formation of oxidized lipids with cellular proteins. The significance of this finding is that vitamin C may help maintain proper function of metabolizing and transporter proteins, thus mitigating the deleterious effects of oxidized lipids.

Structure elucidation and biological activity of phytochemicals

Our laboratory also has interests in the biological effects of phytochemicals. We have explored the chemistry and biology of prenylated flavonoids of the hop plant (Humulus lupulus) since 1995. We were the first to report that the principal prenylated flavonoid in hops, xanthohumol, exerts anti-inflammatory and cancer chemopreventive activities. Our current aim is to determine whether and how xanthohumol improves dysfunctional lipid and glucose metabolism in humans diagnosed with metabolic syndrome.

Another research project in our laboratory is focused on the chemistry and biology of phytochemicals from the oilseed crop, meadowfoam (Limnanthes alba). The Oregon oilseed industry produces a high-quality oil from meadowfoam seeds that is used in personal care products. Considered useless in the past, the seed waste may prove of value as a natural herbicide in organic farming. We have developed a fermentation procedure for enhancing the herbicidal activity of the seed waste by converting inactive seed-meal glucosinolates into degradation products with herbicidal activity.

Vitamin E in Human Health

Principal Investigator: Maret G. Traber, Ph.D.

Our laboratory investigates vitamin E. Why do we need it? How much do we need? What is the best way to consume it? Are there adverse effects from consuming too much? Nearly 100 years after the discovery of vitamin E, we recognize that α-tocopherol is required for human life, functions as a potent fat-soluble antioxidant, and is regulated by the human body. A protein in the liver, the α-tocopherol transfer protein (α-TTP), is critical to maintain adequate vitamin E concentrations in the body. We have discovered that this protein is also necessary in the developing brain, likely to deliver vitamin E as the brain is forming. To do these studies we use the zebrafish because its genes are similar to many of those in humans. Using the zebrafish model, we are now seeking to better define the functional role of α-tocopherol by studying vitamin E deficiency.

At the other extreme, we also study vitamin E excess. We have found that vitamin E metabolism serves to prevent excess accumulation of vitamin E in the body. We are currently investigating how these mechanisms might have adverse effects with respect to vitamin K metabolism. Overall, the assessment of the delivery and function of vitamin E in humans has lagged because previously we lacked the appropriate tools. We are in the process of developing an intravenous preparation of vitamin E labeled with deuterium to be able, for the first time, to measure the absorption, biokinetics, and bioavailability of vitamin E in humans.