Columbia, MO, United States
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Heden T.D.,University of Missouri | Morris E.M.,Harry uman Memorial Veterans Medical Center | Kearney M.L.,University of Missouri | Liu T.-W.,University of Missouri | And 4 more authors.
Applied Physiology, Nutrition and Metabolism | Year: 2014

The purpose of this study was to compare the effects of short-term low-fat (LF) and high-fat (HF) diets on fed-state hepatic triacylglycerol (TAG) secretion, the content of proteins involved in TAG assembly and secretion, fatty acid oxidation (FAO), and the fatty acid profile of stored TAG. Using selectively bred obese-prone Sprague-Dawley rats, we directly measured fed-state hepatic TAG secretion, using Tyloxapol (a lipoprotein lipase inhibitor) and a standardized oral mixed meal (45% carbohydrate, 40% fat, 15% protein) bolus in animals fed a HF or LF diet for 2 weeks, after which the rats were maintained on their respective diet for 1 week (washout) prior to the liver being excised to measure protein content, FAO, and TAG fatty acid profiles. Hepatic DGAT-1 protein expression was ~27% lower in HF- than in LF-fed animals (p < 0.05); the protein expression of all other molecules was similar in the 2 diets. The fed-state hepatic TAG secretion rate was ~39% lower (p < 0.05) in HF- (4.62 ± 0.18 mmol·h-1) than in LF- (7.60 ± 0.57 mmol·h-1) fed animals. Hepatic TAG content was ~2-fold higher (p < 0.05) in HF- (1.07 ± 0.15 nmol·g-1 tissue) than in LF- (0.50 ± 0.16 nmol·g-1 tissue) fed animals. In addition, the fatty acid profile of liver TAG in HF-fed animals closely resembled the diet, whereas in LF-fed animals, the fatty acid profile consisted of mostly de novo synthesized fatty acids. FAO was not altered by diet. LF and HF diets differentially alter fed-state hepatic TAG secretion, hepatic fatty acid profiles, and DGAT-1 protein expression.


Rector R.S.,University of Missouri | Rector R.S.,Harry uman Memorial Veterans Medical Center | Thyfault J.P.,University of Missouri | Thyfault J.P.,Harry uman Memorial Veterans Medical Center
Journal of Applied Physiology | Year: 2011

While physical activity represents a key element in the prevention and management of many chronic diseases, we and others believe that physical inactivity is a primary cause of obesity and associated metabolic disorders. Unfortunately, accumulating evidence suggests that we have engineered physical activity out of our normal daily living activity. One such consequence of our sedentary and excessive lifestyle is nonalcoholic fatty liver disease (NAFLD), which is now considered the most common cause of chronic liver disease in Westernized societies. In this review, we will present evidence that physical inactivity, low aerobic fitness, and overnutrition, either separately or in combination, are an underlying cause of NAFLD. Copyright © 2011 the American Physiological Society.


Rector R.S.,Harry uman Memorial Veterans Medical Center | Rector R.S.,University of Missouri | Morris E.M.,Harry uman Memorial Veterans Medical Center | Morris E.M.,University of Missouri | And 8 more authors.
Hepatology | Year: 2013

Earlier reports suggest a link between mitochondrial dysfunction and development of hepatic insulin resistance. Here we used a murine model heterozygous (HET) for a mitochondrial trifunctional protein (MTP) gene defect to determine if a primary defect in mitochondrial long-chain fatty acid oxidation disrupts hepatic insulin action. Hyperinsulinemic-euglycemic clamps and signaling studies were performed for assessment of whole-body and hepatic insulin resistance/signaling. In addition, hepatic fatty acid oxidation and hepatic insulin action were assessed in vitro using primary hepatocytes isolated from HET and wildtype (WT) mice. In both hepatic mitochondria and isolated primary hepatocytes, heterozygosity of MTP caused an ∼50% reduction in mitochondrial fatty acid oxidation, a significantly impaired glucose disposal during the insulin clamp, and a markedly lower insulin-stimulated suppression of hepatic glucose production. HET mice also exhibited impaired insulin signaling, with increased hepatic phosphorylation of IRS2 (ser731) and reduced Akt phosphorylation (ser473) in both hepatic tissue and isolated primary hepatocytes. Assessment of insulin-stimulated FOXO1/phospho-FOXO1 protein content and PEPCK/G6Pase messenger RNA (mRNA) expression did not reveal differences between HET and WT mice. However, insulin-induced phosphorylation of GSK3β was significantly blunted in HET mice. Hepatic insulin resistance was associated with an increased methylation status of the catalytic subunit of protein phosphatase 2A (PP2A-C), but was not associated with differences in hepatic diacylglycerol content, activated protein kinase C-ε{lunate} (PKC-ε{lunate}), inhibitor κB kinase β (IKK-β), c-Jun N-terminal kinase (JNK), or phospho-JNK protein contents. Surprisingly, hepatic ceramides were significantly lower in the HET mice compared with WT. Conclusion: A primary defect in mitochondrial fatty acid β-oxidation causes hepatic insulin resistance selective to hepatic glycogen metabolism that is associated with elevated methylated PP2A-C, but independent of other mechanisms commonly considered responsible for insulin resistance. © 2013 American Association for the Study of Liver Diseases.


Matthew Morris E.,University of Missouri | Matthew Morris E.,Harry uman Memorial Veterans Medical Center | Fletcher J.A.,University of Missouri | Fletcher J.A.,Harry uman Memorial Veterans Medical Center | And 4 more authors.
Molecular and Cellular Endocrinology | Year: 2013

Nonalcoholic fatty liver disease (NAFLD) is now considered the most prevalent chronic liver disease, affecting over 30% of the US adult population. NAFLD is strongly linked to insulin resistance and is considered the hepatic manifestation of the metabolic syndrome. Activation of the renin-angiotensin-aldosterone system (RAAS) is known to play a role in the hypertension observed in the metabolic syndrome and also is thought to play a central role in insulin resistance and NAFLD. Angiotensin II (AngII) is considered the primary effector of the physiological outcomes of RAAS signaling, both at the systemic and local tissue level. Herein, we review data describing the potential involvement of AngII-mediated signaling at multiple levels in the development and progression of NAFLD, including increased steatosis, inflammation, insulin resistance, and fibrosis. Additionally, we present recent work on the potential therapeutic benefits of RAAS and angiotensin II signaling inhibition in rodent models and patients with NAFLD. © 2012 Elsevier Ireland Ltd.


Fletcher J.A.,University of Missouri | Fletcher J.A.,Harry uman Memorial Veterans Medical Center | Meers G.M.,Harry uman Memorial Veterans Medical Center | Meers G.M.,University of Missouri | And 7 more authors.
Applied Physiology, Nutrition and Metabolism | Year: 2012

Chronic treatment with fibroblast growth factor 21 (FGF-21) favorably improves obesity and nonalcoholic fatty liver disease (NAFLD) outcomes; however, FGF-21 expression is paradoxically elevated in obese conditions. Here, we sought to determine the effects of obesity prevention by daily exercise (EX) vs. caloric restriction (CR) on hepatic FGF-21 in the hyperphagic, Otsuka Long-Evans Tokushima Fatty (OLETF) rat. Four-week-old male OLETF rats were randomized into groups (n = 7-8 per group) of ad libitum fed, sedentary (OLETF-SED), voluntary wheel running exercise (OLETFEX), or CR (OLETF-CR; 70% of SED) until 40 weeks of age. Nonhyperphagic, Long-Evans Tokushima Otsuka (LETOSED) rats served as controls. Both daily EX and CR prevented obesity and NAFLD development observed in the OLETFSED animals. This was associated with significantly (p < 0.01) lower serum FGF-21 (~80% lower) and hepatic FGF-21 mRNA expression (~65% lower) in the OLETF-EX and OLETF-CR rats compared with the OLETF-SED rats. However, hepatic FGF-21 protein content was reduced to the greatest extent in the OLETF-EX animals (50% of OLETF-SED) and did not differ between the OLETF-SED and OLETF-CR rats. Hepatic FGF-21 signaling mediators - hepatic FGF-21 receptor 2 (FGFR2, mRNA expression), hepatic FGF-21 receptor substrate 2 (FRS2, protein content), and co-receptor β-Klotho (protein content) - were all elevated (60%-100%, ~40%, and +30%-50%, respectively) in the OLETF-EX and OLETF-CR animals compared with the OLETF-SED animals. Daily exercise and caloric restriction modulate hepatic FGF-21 and its primary signaling mediators in the hyperphagic OLETF rat. Enhanced metabolic action of FGF-21 may partially explain the benefits of exercise and caloric restriction on NAFLD outcomes.


Perfield J.W.,University of Missouri | Ortinau L.C.,University of Missouri | Pickering R.T.,University of Missouri | Ruebel M.L.,University of Missouri | And 4 more authors.
Journal of Obesity | Year: 2013

Nonalcoholic fatty liver disease (NAFLD) is strongly linked to obesity, insulin resistance, and abnormal hepatic lipid metabolism; however, the precise regulation of these processes remains poorly understood. Here we examined genes and proteins involved in hepatic oxidation and lipogenesis in 14-week-old leptin-deficient Ob/Ob mice, a commonly studied model of obesity and hepatic steatosis. Obese Ob/Ob mice had increased fasting glucose, insulin, and calculated HOMA-IR as compared with lean wild-type (WT) mice. Ob/Ob mice also had greater liver weights, hepatic triglyceride (TG) content, and markers of de novo lipogenesis, including increased hepatic gene expression and protein content of acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and stearoyl-CoA desaturase-1 (SCD-1), as well as elevated gene expression of PPARγ and SREBP-1c compared with WT mice. While hepatic mRNA levels for PGC-1α, PPARα, and TFAM were elevated in Ob/Ob mice, measures of mitochondrial function (β-HAD activity and complete (to CO2) and total mitochondrial palmitate oxidation) and mitochondrial OXPHOS protein subunits I, III, and V content were significantly reduced compared with WT animals. In summary, reduced hepatic mitochondrial content and function and an upregulation in de novo lipogenesis contribute to obesity-associated NAFLD in the leptin-deficient Ob/Ob mouse. © 2013 James W. Perfield II et al.


Morris E.M.,University of Missouri | Rector R.S.,University of Missouri | Rector R.S.,Harry uman Memorial Veterans Medical Center | Thyfault J.P.,University of Missouri | And 3 more authors.
Antioxidants and Redox Signaling | Year: 2011

Alcoholic and nonalcoholic fatty liver diseases are potentially pathological conditions that can progress to steatohepatitis, fibrosis, and cirrhosis. These conditions affect millions of people throughout the world in part through poor lifestyle choices of excess alcohol consumption, overnutrition, and lack of regular physical activity. Abnormal mitochondrial and cellular redox homeostasis has been documented in steatohepatitis and results in alterations of multiple redox-sensitive signaling cascades. Ultimately, these changes in signaling lead to altered enzyme function and transcriptional activities of proteins critical to mitochondrial and cellular function. In this article, we review the current hypotheses linking mitochondrial redox state to the overall pathophysiology of alcoholic and nonalcoholic steatohepatitis and briefly discuss the current therapeutic options under investigation. © Copyright 2011, Mary Ann Liebert, Inc.


Rector R.S.,University of Missouri | Thyfault J.P.,University of Missouri | Thyfault J.P.,Harry uman Memorial Veterans Medical Center | Uptergrove G.M.,University of Missouri | And 9 more authors.
Journal of Hepatology | Year: 2010

Background & Aims: In this study, we sought to determine the temporal relationship between hepatic mitochondrial dysfunction, hepatic steatosis and insulin resistance, and to examine their potential role in the natural progression of non-alcoholic fatty liver disease (NAFLD) utilising a sedentary, hyperphagic, obese, Otsuka Long-Evans Tokushima Fatty (OLETF) rat model. Methods: OLETF rats and their non-hyperphagic control Long-Evans Tokushima Otsuka (LETO) rats were sacrificed at 5, 8, 13, 20, and 40 weeks of age (n = 6-8 per group). Results: At 5 weeks of age, serum insulin and glucose and hepatic triglyceride (TG) concentrations did not differ between animal groups; however, OLETF animals displayed significant (p <0.01) hepatic mitochondrial dysfunction as measured by reduced hepatic carnitine palmitoyl-CoA transferase-1 activity, fatty acid oxidation, and cytochrome c protein content compared with LETO rats. Hepatic TG levels were significantly elevated by 8 weeks of age, and insulin resistance developed by 13 weeks in the OLETF rats. NAFLD progressively worsened to include hepatocyte ballooning, perivenular fibrosis, 2.5-fold increase in serum ALT, hepatic mitochondrial ultrastructural abnormalities, and increased hepatic oxidative stress in the OLETF animals at later ages. Measures of hepatic mitochondrial content and function including β-hydroxyacyl-CoA dehydrogenase activity, citrate synthase activity, and immunofluorescence staining for mitochondrial carbamoyl phosphate synthetase-1, progressively worsened and were significantly reduced at 40 weeks in OLETF rats compared to LETO animals. Conclusions: Our study documents that hepatic mitochondrial dysfunction precedes the development of NAFLD and insulin resistance in the OLETF rats. This evidence suggests that progressive mitochondrial dysfunction contributes to the natural history of obesity-associated NAFLD. © 2010 European Association for the Study of the Liver.


Linden M.A.,Harry uman Memorial Veterans Medical Center | Linden M.A.,University of Missouri | Fletcher J.A.,Harry uman Memorial Veterans Medical Center | Fletcher J.A.,University of Missouri | And 7 more authors.
American Journal of Physiology - Gastrointestinal and Liver Physiology | Year: 2016

Hyperphagic Otsuka Long-Evans Tokushima fatty (OLETF) rats develop obesity, insulin resistance, and nonalcoholic fatty liver disease (NAFLD), but lifestyle modifications, such as caloric restriction (CR), can prevent these conditions. We sought to determine if prior CR had protective effects on metabolic health and NAFLD development following a 4-wk return to ad libitum (AL) feeding. Four-week-old male OLETF rats (n = 8–10/group) were fed AL for 16 wk (O-AL), CR for 16 wk (O-CR; ~70% kcal of O-AL), or CR for 12 wk followed by 4 wk of AL feeding (O-AL4wk). CR-induced benefit in prevention of NAFLD, including reduced hepatic steatosis, inflammation, and markers of Kupffer cell activation/number, was largely lost in AL4wk rats. These findings occurred in conjunction with a partial loss of CR-induced beneficial effects on obesity and serum triglycerides in O-AL4wk rats, but in the absence of changes in serum glucose or insulin. CR-induced increases in hepatic mitochondrial respiration remained significantly elevated (P < 0.01) in O-AL4wk compared with O-AL rats, while mitochondrial [1-14C]palmitate oxidation, citrate synthase activity, and β-hydroxyacyl-CoA dehydrogenase activity did not differ among OLETF groups. NAFLD development in O-AL4wk rats was accompanied by increases in the protein content of the de novo lipogenesis markers fatty acid synthase and stearoyl-CoA desaturase-1 and decreases in phosphorylated acetyl- CoA carboxylase (pACC)/ACC compared with O-CR rats (P < 0.05 for each). The beneficial effects of chronic CR on NAFLD development were largely lost with 4 wk of AL feeding in the hyperphagic OLETF rat, highlighting the importance of maintaining energy balance in the prevention of NAFLD. © 2016 the American Physiological Society.


PubMed | Harry uman Memorial Veterans Medical Center
Type: Journal Article | Journal: Hepatology (Baltimore, Md.) | Year: 2013

Earlier reports suggest a link between mitochondrial dysfunction and development of hepatic insulin resistance. Here we used a murine model heterozygous (HET) for a mitochondrial trifunctional protein (MTP) gene defect to determine if a primary defect in mitochondrial long-chain fatty acid oxidation disrupts hepatic insulin action. Hyperinsulinemic-euglycemic clamps and signaling studies were performed for assessment of whole-body and hepatic insulin resistance/signaling. In addition, hepatic fatty acid oxidation and hepatic insulin action were assessed in vitro using primary hepatocytes isolated from HET and wildtype (WT) mice. In both hepatic mitochondria and isolated primary hepatocytes, heterozygosity of MTP caused an 50% reduction in mitochondrial fatty acid oxidation, a significantly impaired glucose disposal during the insulin clamp, and a markedly lower insulin-stimulated suppression of hepatic glucose production. HET mice also exhibited impaired insulin signaling, with increased hepatic phosphorylation of IRS2 (ser731) and reduced Akt phosphorylation (ser473) in both hepatic tissue and isolated primary hepatocytes. Assessment of insulin-stimulated FOXO1/phospho-FOXO1 protein content and PEPCK/G6Pase messenger RNA (mRNA) expression did not reveal differences between HET and WT mice. However, insulin-induced phosphorylation of GSK3 was significantly blunted in HET mice. Hepatic insulin resistance was associated with an increased methylation status of the catalytic subunit of protein phosphatase 2A (PP2A-C), but was not associated with differences in hepatic diacylglycerol content, activated protein kinase C- (PKC-), inhibitor B kinase (IKK-), c-Jun N-terminal kinase (JNK), or phospho-JNK protein contents. Surprisingly, hepatic ceramides were significantly lower in the HET mice compared with WT.A primary defect in mitochondrial fatty acid -oxidation causes hepatic insulin resistance selective to hepatic glycogen metabolism that is associated with elevated methylated PP2A-C, but independent of other mechanisms commonly considered responsible for insulin resistance. (HEPATOLOGY 2013;).

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