Intrinsic high aerobic capacity protects against lipid induced hepatic insulin resistance [abstract]

Hepatic steatosis is commonly linked to hepatic insulin resistance. However, recent studies have found that increased hepatic triacylglycerol (TAG) accumulation is not always associated with impaired hepatic insulin signaling, leading to a hypothesis that partitioning of lipids into TAG in the liver matched with high rates of fatty acid oxidation (FAO) under high lipid exposure conditions may protect against hepatic insulin resistance. We examined this hypothesis in the livers of high and low capacity running (HCR/LCR) rats which were created by artificial selection based on differences in intrinsic aerobic capacity

Interdisciplinary Approach to Examine the Effects of Lifestyle Modifications on Nonalcoholic Fatty Liver Disease

Comparative Medicine - OneHealth and Comparative Medicine Poster SessionA critical complication of the obesity epidemic experienced in Westernized societies is nonalcoholic fatty liver disease (NAFLD). NAFLD, fatty liver not due to alcohol consumption, is the most common chronic liver disease and associated with increasing morbidity, mortality, and demand for liver transplantation. NAFLD is a progressive disease with a histological spectrum ranging from hepatic steatosis to nonalcoholic steatohepatitis, advanced fibrosis, and cirrhosis. Approximately one third of all US adults (90 million) have fatty livers, with prevalence rates as high as 75-100% in the obese and morbidly obese. With growing health problems associated with NAFLD, major questions facing research scientists and health care providers are what are the mechanisms responsible for NAFLD development and what is the best treatment strategy. Since drug interventions appear to be only marginally successful, the cornerstone therapy for NAFLD remains lifestyle modifications of exercise and weight loss. However, while recent cross-sectional observations suggest that being more physically active is inversely associated with NAFLD, studies which attempt to identify molecular mechanisms underlying the effects of lifestyle modifications on NAFLD are lacking. To address these clinical questions, we have taken an interdisciplinary approach with collaborations from experts in multiple departments and facilities at the University of Missouri, including Nutrition and Exercise Physiology, Hepatology, Veterinary Biomedical Sciences, and VA investigators. In addition, we have utilized a unique animal model, the hyperphagic Otsuka Long-Evans Tokushima Fatty (OLETF) rat that develops obesity, insulin resistance and overt type 2 diabetes, a model which we liken to overeating, sedentary, obese humans. Through a series of experiments, we found that the natural progression pattern of fatty liver disease in the sedentary OLETF rat closely resembles the human condition (progression from simple hepatic steatosis to hepatocyte ballooning, fibrosis, and inflammation). We also have compelling evidence that hepatic mitochondrial dysfunction is present at an early age and mitochondrial content, function, and mitochondrial health are disrupted with disease progression, suggesting a potential primary event in NAFLD in this animal model. However and perhaps even more important, when OLETF rats are given access to voluntary running wheels and allowed to exercise daily, the initiation and progression of NAFLD is completely prevented. These benefits occur through modification in both peripheral and hepatic factors, including maintenance of glycemic control and enhancement of hepatic mitochondrial content and function. We are currently in the process of translating these very exciting findings in a randomized, human clinical trial examining the impact of different lifestyle modifications in the treatment of NAFLD. Findings from our research group have important public health application, particularly for the 60-80% of Americans who overeat, who are overweight, and who are physically inactive

PGC-1[alpha] overexpression in primary hepatocytes increases fatty acid oxidation and mitochondrial content [abstract]

The role of peroxisome proliferator-activated receptor-[gamma] coactivator-1[alpha] (PGC-1[alpha]) in increasing mitochondrial content and fatty acid oxidation (FAO) in skeletal muscle has been well described. Often, this increase in mitochondrial content and FAO is observed to associate with increased skeletal muscle and systemic insulin sensitivity. However, to date no studies have documented the effect of elevated PGC-1[alpha] protein expression on hepatocyte mitochondrial function and FAO. Therefore, we examined whether adenoviral PGC-1alpha] protein overexpression would result in increased markers of mitochondrial content and FAO in primary hepatocytes. Additionally, would the increased mitochondrial content and FAO be associated with protection of hepatocyte insulin signaling following chronic exposure to lipids

Oxidative Stress-Mediated Mitochondrial Dysfunction Contributes to Angiotensin II-Induced Nonalcoholic Fatty Liver Disease in Transgenic Ren2 Rats

Emerging evidence indicates that impaired mitochondrial fatty acid β-oxidation plays a key role in liver steatosis. We have recently demonstrated that increased angiotensin (ANG) II causes progressive hepatic steatosis associated with oxidative stress; however, the underlying mechanisms remain unclear. We hypothesized that ANG II causes hepatic mitochondrial oxidative damage and impairs mitochondrial β-oxidation, thereby leading to hepatic steatosis. We used the Ren2 rat with elevated endogenous ANG II levels to evaluate mitochondrial ultrastructural changes, gene expression levels, and β-oxidation. Compared with Sprague-Dawley littermates, Ren2 livers exhibited mitochondrial damage and reduced β-oxidation, as evidenced by ultrastructural abnormalities, decrease of mitochondrial content, percentage of palmitate oxidation to CO2, enzymatic activities (β-HAD and citrate synthase), and the expression levels of cytochrome c, cytochrome c oxidase subunit 1, and mitochondrial transcription factor A. These abnormalities were improved with either ANG II receptor blocker valsartan or superoxide dismutase/catalase mimetic tempol treatment. Both valsartan and tempol substantially attenuated mitochondrial lipid peroxidation in Ren2 livers. Interestingly, there was no difference in the expression of key enzymes (ACC1 and FAS) for fatty acid syntheses and their transcription factors (SREBP-1c and ChREBP) between Sprague-Dawley, untreated Ren2, and valsartan- or tempol-treated Ren2 rats. These results document that ANG II induces mitochondrial oxidative damage and impairs mitochondrial β-oxidation, contributing to liver steatosis