Non-alcoholic fatty liver disease (NAFLD) can progress to include nonalcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. NAFLD is also implicated in the development of hepatic insulin resistance, a primary player in the development of type 2 diabetes. Recent clinical data demonstrates that patients with low aerobic fitness have increased susceptibility for the development of NAFLD. In addition, evidence from our research group and others has implicated hepatic mitochondrial dysfunction as a primary feature in the development of both NAFLD and hepatic insulin resistance. Our preliminary evidence implicates hepatic mitochondrial dysfunction (low mitochondrial content and reduced fatty acid oxidation (FAOX) as the link between low aerobic fitness and increased susceptibility for both NAFLD and hepatic insulin resistance. However, the links between these factors and the underlying mechanism(s) by which mitochondrial dysfunction leads to NAFLD remain unknown. To unravel these links, we will study two novel strains of rats [high or low capacity runners (HCR/LCR)] with 30% different intrinsic aerobic fitness levels due to two-way divergent selective breeding. The low fit-LCR rat displays reduced mitochondrial content and fatty acid oxidation (FAOX) and NAFLD at a young age and significantly greater hepatic injury compared to the high fit-HCR livers. Thus, the high fit-HCR and low fit-LCR strains provide a novel experimental platform to study the role of aerobic fitness on liver metabolism. The central hypothesis of this proposal is that low aerobic fitness leads to increased risk of NAFLD and hepatic insulin resistance because of mitochondrial dysfunction.
The specific aims are the following:
Aim 1) to test if the low fit-LCR rats have increased susceptibility to lipid induced NAFLD and NASH, and if this can be prevented by increasing either mitochondrial content or FAOX.
Aim 2) to test if the low fit-LCR rats have hepatic insulin resistance and dysregulated hepatic glucose output due to mitochondrial dysfunction or due to NAFLD.
Both Aim 1 and Aim 2 will utilize dietary high fat in-vivo studies and lipid overload in-vitro studies (primary hepatocytes) to examine susceptibility for NAFLD and insulin resistance in low aerobically fit LCR and high aerobically fit HCR animals. In addition, hepatic insulin resistance will be studied with in-vitro insulin signaling and in-vivo hyperinsulinemic-euglycemic clamp methods. We will also evaluate if adenoviral overexpression of peroxisome proliferator gamma co-activator 1 alpha (PGC-1, to stimulate mitochondrial biogenesis) or carnitine palmitoyltransferase-1 (CPT-1, to enhance FAOX in existing mitochondria) in LCR livers or primary hepatocytes can protect against lipid induced NAFLD and improve hepatic insulin sensitivity. The outcomes of this study will provide a greater mechanistic understanding of the links between aerobic fitness, hepatic mitochondrial function, and NAFLD. The outcomes will also if determine if increased hepatic mitochondrial content or increased hepatic fatty acid oxidation are effective therapeutic targets to prevent NAFLD or hepatic insulin resistance.
Currently, 34% of the general population (10) and 75-100% of obese and extremely obese individuals are estimated to have fatty liver (4). The outcomes of this study will provide therapeutic targets for the treatment or prevention of non-alcoholic fatty liver disease and insulin resistance, and discover the molecular/biochemical role of whole body aerobic fitness in the liver.
|Thyfault, John P; Du, Mengmeng; Kraus, William E et al. (2015) Physiology of sedentary behavior and its relationship to health outcomes. Med Sci Sports Exerc 47:1301-5|
|Reynolds, Leryn J; Credeur, Daniel P; Holwerda, Seth W et al. (2015) Acute inactivity impairs glycemic control but not blood flow to glucose ingestion. Med Sci Sports Exerc 47:1087-94|
|Linden, Melissa A; Fletcher, Justin A; Morris, E Matthew et al. (2015) Treating NAFLD in OLETF rats with vigorous-intensity interval exercise training. Med Sci Sports Exerc 47:556-67|
|Crissey, Jacqueline M; Jenkins, Nathan T; Lansford, Kasey A et al. (2014) Adipose tissue and vascular phenotypic modulation by voluntary physical activity and dietary restriction in obese insulin-resistant OLETF rats. Am J Physiol Regul Integr Comp Physiol 306:R596-606|
|Booth, Frank W; Thyfault, John P (2014) Timing and intensity of exercise for glucose control. Reply to Chacko E. [letter]. Diabetologia 57:2427|
|Fletcher, Justin A; Meers, Grace M; Linden, Melissa A et al. (2014) Impact of various exercise modalities on hepatic mitochondrial function. Med Sci Sports Exerc 46:1089-97|
|Linden, Melissa A; Fletcher, Justin A; Morris, E Matthew et al. (2014) Combining metformin and aerobic exercise training in the treatment of type 2 diabetes and NAFLD in OLETF rats. Am J Physiol Endocrinol Metab 306:E300-10|
|Oberlin, Douglas J; Mikus, Catherine R; Kearney, Monica L et al. (2014) One bout of exercise alters free-living postprandial glycemia in type 2 diabetes. Med Sci Sports Exerc 46:232-8|
|Morris, E Matthew; Jackman, Matthew R; Johnson, Ginger C et al. (2014) Intrinsic aerobic capacity impacts susceptibility to acute high-fat diet-induced hepatic steatosis. Am J Physiol Endocrinol Metab 307:E355-64|
|Linden, Melissa A; Meers, Grace M; Ruebel, Meghan L et al. (2013) Hepatic steatosis development with four weeks of physical inactivity in previously active, hyperphagic OLETF rats. Am J Physiol Regul Integr Comp Physiol 304:R763-71|
Showing the most recent 10 out of 11 publications