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Rohit Kohli,
Kenneth Dr Setchell,
Michelle Kirby,
Andriy Myronovych,
Karen K Ryan,
Samar H Ibrahim,
Jose Berger,
Kathi Smith,
Mouhamadoul Toure,
Stephen C Woods,
Randy J Seeley
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ABSTRACT: Bariatric surgery elevates serum bile acids. Conjugated bile acid administration, such as tauroursodeoxycholic acid (TUDCA), improves insulin sensitivity, while short-circuiting bile acid circulation through ileal interposition surgery in rats raises TUDCA levels. We hypothesized that bariatric surgery outcomes could be recapitulated by short-circuiting the normal entero-hepatic bile circulation. We established a model wherein male obese rats underwent either bile diversion (BD) or Sham (SH) surgery. The BD group had a catheter inserted into the common bile duct and its distal end anchored into the mid-distal jejunum for 4-5 weeks. Glucose tolerance, insulin and glucagon-like peptide-1 (GLP-1) response, hepatic steatosis and endoplasmic reticulum (ER) stress were measured. Rats' post-BD lost significantly more weight than the SH-rats. BD rats gained less fat mass post-surgery. BD rats had improved glucose tolerance, increased higher post-prandial GLP-1 response and serum bile acids but less liver steatosis. Serum bile acid levels including TUDCA concentrations were higher in BD compared to SH pair-fed rats. Fecal bile acid levels were not different. Liver ER stress (CHOP mRNA and pJNK protein) was decreased in BD rats. Bile acid gavage (TUDCA/UDCA) in diet-induced obese rats, elevated serum TUDCA and concomitantly reduced hepatic steatosis and ER stress (CHOP mRNA). These data demonstrate the ability of alterations in bile acids to recapitulate important metabolic improvements seen after bariatric surgery. Further, our work establishes a model for focused study of bile acids in the context of bariatric surgery that may lead to the identification of therapeutics for metabolic disease.
Endocrinology 04/2013; · 4.46 Impact Factor
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ABSTRACT: Weight loss is an effective treatment for children with non-alcoholic fatty liver disease (NAFLD) but it is very difficult to achieve outside of an intensive weight management program. We hypothesized that one can achieve success in improving NAFLD and weight-related outcomes in a structured and focused multidisciplinary clinical program feasible to implement in a gastroenterology clinic. METHODS:: We prospectively tracked the clinical status of our patients enrolled in a multidisciplinary program of dietary and exercise advice through an Institutional Review Board-approved NAFLD registry. Each patient met with a gastroenterologist and dietician every 3 months for 30 minutes to set individualized goals and monitor progress. RESULTS:: 108 children have been enrolled in the registry and of the 83 that were eligible for 1 year follow-up and included in the analysis, 39 patients returned, resulting in a 47% follow-up rate. These 39 patients showed statistically significant improvements in mean BMI z-score (-0.1 units, p < 0.05), total (-11 mg/dL, p < 0.05) and low density lipoprotein cholesterol (-9 mg/dL, p < 0.05), and serum alanine aminotransferase (ALT) levels (-36 U/L) and aspartate amino transferase (AST) levels (-22 U/L) levels. CONCLUSION:: A clinically feasible multidisciplinary program of every 3 month 30 minute visits to set and monitor nutrition and exercise goals, stabilized mean BMI z-score and significantly improved aminotransferase levels at 1 year follow-up in obese pediatric patients with NAFLD.
Journal of pediatric gastroenterology and nutrition 03/2013; · 2.18 Impact Factor
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ABSTRACT: Fibroblast growth factor-19 (FGF19) and its rodent ortholog, FGF15, are hormones produced in the distal small intestine and secreted into the circulation after a meal. In addition to controlling the enterohepatic circulation of bile acids, FGF15/19 also regulates systemic lipid and glucose metabolism. In these experiments we investigated the hypothesis that, like other gut-derived postprandial hormones, FGF15/19 can act in the central nervous system to elicit its metabolic effects. We found that FGF-receptors 1 and 4 are present in rat hypothalamus, and that their expression was reduced by up to 60% in high-fat fed rats relative to lean controls. Consistent with a potential role for brain FGF15/19 signaling to regulate energy and glucose homeostasis, and with a previous report that intracerebroventricular (i.c.v.) administration of FGF19 increases energy expenditure, we report that acute i.c.v. FGF19 reduces 24-h food intake and body weight, and acutely improves glucose tolerance. Conversely, i.c.v. administration of an FGF-receptor inhibitor increases food intake and impairs glucose tolerance, suggesting a physiological role for brain FGF receptor signaling. Together, these findings identify the central nervous system as a potentially important target for the beneficial effects of FGF19 in the treatment of obesity and diabetes.
Endocrinology 11/2012; · 4.46 Impact Factor
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ABSTRACT: Squires JE, Sisk RA, Balistreri WF, Kohli R. Isolated unilateral cytomegalovirus retinitis: A rare long-term complication after pediatric liver transplantation. Abstract: To highlight the rare yet devastating complication of CMV retinitis in a minimally immunosuppressed patient eight yr after liver transplantation for biliary atresia. A 22-yr-old female status-post deceased donor liver transplant at age 13 secondary to biliary atresia receiving single agent immunosuppression presented with acute, unilateral, profound decrease in visual acuity. The patient was diagnosed to have acute onset unilateral CMV retinitis. Retinal examination uncovered classical appearance of retinal whitening and retinal hemorrhages with extensive macular involvement. CMV retinitis can occur as a late complication following liver transplantation. Additionally, CMV retinal disease can occur in the absence of laboratory evidence of CMV infection and independent of additional clinical features suggesting CMV disease. Currently, there is no standard of care regarding screening for CMV retinitis, and thus, further research is needed to define the need for potential changes in current clinical practices and post-transplant screening protocols.
Pediatric Transplantation 06/2012; · 1.48 Impact Factor
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The Journal of pediatrics 06/2012; 161(4):579-81. · 4.02 Impact Factor
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ABSTRACT: The world's population is increasingly overweight and obese. According to the World Health Organization (WHO) as of 2010, 43 million children under the age of five were overweight. Once considered to be limited to developed countries, overweight and obese children are now found in low- and middle-income countries, though most commonly in urban areas. Furthermore the WHO now cites the conditions of overweight and obesity as being associated with more deaths around the globe than those associated with being underweight. With this increased prevalence of overweight and obese children has come a host of other medical problems including nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). This review will focus on NAFLD and NASH, their definitions, epidemiology, diagnosis and treatment. The authors will also discuss NAFLD in the Indian subcontinent, and the future of NAFLD and NASH.
The Indian Journal of Pediatrics 06/2012; · 0.52 Impact Factor
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ABSTRACT: Fatty liver disease (FLD) is commonly associated with insulin resistance and obesity, but interestingly it is also observed at low insulin states, such as prolonged fasting. Thus, we asked whether insulin is an independent modulator of hepatic lipid accumulation.
In mice we induced, hypo- and hyperinsulinemia associated FLD by diet induced obesity and streptozotocin treatment, respectively. The mechanism of free fatty acid induced steatosis was studied in cell culture with mouse liver cells under different insulin concentrations, pharmacological phosphoinositol-3-kinase (PI3K) inhibition and siRNA targeted gene knock-down. We found with in vivo and in vitro models that lipid storage is increased, as expected, in both hypo- and hyperinsulinemic states, and that it is mediated by signaling through either insulin receptor substrate (IRS) 1 or 2. As previously reported, IRS-1 was up-regulated at high insulin concentrations, while IRS-2 was increased at low levels of insulin concentration. Relative increase in either of these insulin substrates, was associated with an increase in liver-specific fatty acid transport proteins (FATP) 2&5, and increased lipid storage. Furthermore, utilizing pharmacological PI3K inhibition we found that the IRS-PI3K pathway was necessary for lipogenesis, while FATP responses were mediated via IRS signaling. Data from additional siRNA experiments showed that knock-down of IRSs impacted FATP levels.
States of perturbed insulin signaling (low-insulin or high-insulin) both lead to increased hepatic lipid storage via FATP and IRS signaling. These novel findings offer a common mechanism of FLD pathogenesis in states of both inadequate (prolonged fasting) and ineffective (obesity) insulin signaling.
PLoS ONE 01/2012; 7(6):e38952. · 4.09 Impact Factor
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Journal of Hepatology 05/2011; 55(4):941-3. · 9.26 Impact Factor
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Christine Carter-Kent,
Elizabeth M Brunt,
Lisa M Yerian,
Naim Alkhouri,
Paul Angulo, Rohit Kohli,
Simon C Ling,
Stavra A Xanthakos,
Peter F Whitington,
Phunchai Charatcharoenwitthaya,
Jason Yap,
Rocio Lopez,
Arthur J McCullough,
Ariel E Feldstein
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ABSTRACT: The relations between hepatic steatosis and histological features of hepatocyte injury in children with nonalcoholic fatty liver disease have yet to be examined. The aims of the present study were to establish associations between steatosis amount, type, and distribution in a well-characterized group of children with biopsy-proven nonalcoholic fatty liver disease (NAFLD).
One hundred eight children with NAFLD seen in 5 centers were studied. Clinical and laboratory data were collected. Hematoxylin-eosin and Masson trichrome stains were evaluated by 2 expert liver pathologists. Steatosis grade (0-3), type (macrovesicular, microvesicular, or mixed), and zone (1, 3, azonal, or panacinar) were determined. The NAFLD activity score and fibrosis stage were determined.
Median patient age was 12 years and median body mass index was 31 kg/m. Fibrosis was present in 87%. The median NAFLD activity score was 4. Mild, moderate, and severe steatosis were present in 42%, 34%, and 24% of biopsies, respectively. Macrovesicular steatosis was present in 81% and mixed steatosis was present in 19%. Panacinar distribution of steatosis was most frequent (40%), followed by azonal (27%). Steatosis grade positively correlated with portal inflammation (P = 0.018). Azonal distribution positively correlated with presence of hepatocyte ballooning (P = 0.03). Biopsies with mixed steatosis were approximately 20 times more likely to have megamitochondria than those with macrovesicular steatosis alone (95% confidence interval 2.3-204.9). There was no relation between steatosis amount, type, or distribution to fibrosis stage.
Specific histological patterns of steatosis in children are associated with histological markers of steatohepatitis. Ballooning and portal inflammation correlated well with features of steatosis.
Journal of pediatric gastroenterology and nutrition 02/2011; 52(2):190-7. · 2.18 Impact Factor
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ABSTRACT: Bariatric surgical procedures have become important therapeutic options for treatment of morbid obesity in both adults and adolescents co-morbidities of obesity such as glucose intolerance, type 2 diabetes (T2DM), metabolic syndrome, steatohepatitis, hyperlipidemia and cardiovascular disease. These co-morbidities of obesity have significant impacts on the overall quality of life of the individual and our society at large. Roux-en-Y gastric bypass (RYGB) and the relatively newer procedures of gastric banding (GB) and vertical sleeve gastrectomy (VSG) have proven to be efficacious in achieving rapid weight loss and reversing the comorbidities of obesity. Unfortunately, bariatric procedures are not without risks including micronutrient deficiency, failure to maintain lost weight, and mortality. Further, the resolution of T2DM has long been understood to precede weight loss, and this finding provides important clues about the physiologic underpinnings of the observation. In order to design more effective, safe, and widely available therapeutics for obesity, important and highly relevant questions need to be addressed regarding mechanisms behind the weight-loss-independent benefits of bariatric surgical procedures. This review will provide an overview of the molecular changes occurring across all biological systems after bariatric surgery including the changes in hepatic, adipocyte and gut derived signals after surgery. We will also discuss existing literature regarding the weight-loss-independent metabolic benefits including improvement in insulin sensitivity and central nervous system integration of these signals.
Reviews in Endocrine and Metabolic Disorders 02/2011; 12(3):211-7. · 3.17 Impact Factor
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Rohit Kohli
The Journal of pediatrics 11/2010; 157(5):766. · 4.02 Impact Factor
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Rohit Kohli,
Michelle Kirby,
Kenneth D R Setchell,
Pinky Jha,
Kori Klustaitis,
Laura A Woollett,
Paul T Pfluger,
William F Balistreri,
Patrick Tso,
Ronald J Jandacek,
Stephen C Woods,
James E Heubi,
Matthias H Tschoep,
David A D'Alessio,
Noah F Shroyer,
Randy J Seeley
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ABSTRACT: Surgical interposition of distal ileum into the proximal jejunum is a bariatric procedure that improves the metabolic syndrome. Changes in intestinal and hepatic physiology after ileal interposition (transposition) surgery (IIS) are not well understood. Our aim was to elucidate the adaptation of the interposed ileum, which we hypothesized, would lead to early bile acid reabsorption in the interposed ileum, thus short circuiting enterohepatic bile acid recycling to more proximal bowel segments. Rats with diet-induced obesity were randomized to IIS, with 10 cm of ileum repositioned distal to the duodenum, or sham surgery. A subgroup of sham rats was pair-fed to IIS rats. Physiological parameters were measured until 6 wk postsurgery. IIS rats ate less and lost more weight for the first 2 wk postsurgery. At study completion, body weights were not different, but IIS rats had reversed components of the metabolic syndrome. The interposed ileal segment adapted to a more jejunum-like villi length, mucosal surface area, and GATA4/ILBP mRNA. The interposed segment retained capacity for bile acid reabsorption and anorectic hormone secretion with the presence of ASBT and glucagon-like-peptide-1-positive cells in the villi. IIS rats had reduced primary bile acid levels in the proximal intestinal tract and higher primary bile acid levels in the serum, suggesting an early and efficient reabsorption of primary bile acids. IIS rats also had increased taurine and glycine-conjugated serum bile acids and reduced fecal bile acid loss. There was decreased hepatic Cyp27A1 mRNA with no changes in hepatic FXR, SHP, or NTCP expression. IIS protects against the metabolic syndrome through short-circuiting enterohepatic bile acid recycling. There is early reabsorption of primary bile acids despite selective "jejunization" of the interposed ileal segment. Changes in serum bile acids or bile acid enterohepatic recycling may mediate the metabolic benefits seen after bariatric surgery.
AJP Gastrointestinal and Liver Physiology 09/2010; 299(3):G652-60. · 3.43 Impact Factor
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Rohit Kohli,
Michelle Kirby,
Stavra A Xanthakos,
Samir Softic,
Ariel E Feldstein,
Vijay Saxena,
Peter H Tang,
Lili Miles,
Michael V Miles,
William F Balistreri,
Stephen C Woods,
Randy J Seeley
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ABSTRACT: Diets high in saturated fat and fructose have been implicated in the development of obesity and nonalcoholic steatohepatitis (NASH) in humans. We hypothesized that mice exposed to a similar diet would develop NASH with fibrosis associated with increased hepatic oxidative stress that would be further reflected by increased plasma levels of the respiratory chain component, oxidized coenzyme Q9 ((ox)CoQ9). Adult male C57Bl/6 mice were randomly assigned to chow, high-fat (HF), or high-fat high-carbohydrate (HFHC) diets for 16 weeks. The chow and HF mice had free access to pure water, whereas the HFHC group received water with 55% fructose and 45% sucrose (wt/vol). The HFHC and HF groups had increased body weight, body fat mass, fasting glucose, and were insulin-resistant compared with chow mice. HF and HFHC consumed similar calories. Hepatic triglyceride content, plasma alanine aminotransferase, and liver weight were significantly increased in HF and HFHC mice compared with chow mice. Plasma cholesterol (P < 0.001), histological hepatic fibrosis, liver hydroxyproline content (P = 0.006), collagen 1 messenger RNA (P = 0.003), CD11b-F4/80+Gr1+ monocytes (P < 0.0001), transforming growth factor beta1 mRNA (P = 0.04), and alpha-smooth muscle actin messenger RNA (P = 0.001) levels were significantly increased in HFHC mice. Hepatic oxidative stress, as indicated by liver superoxide expression (P = 0.002), 4-hydroxynonenal, and plasma (ox)CoQ9 (P < 0.001) levels, was highest in HFHC mice. CONCLUSION: These findings demonstrate that nongenetically modified mice maintained on an HFHC diet in addition to developing obesity have increased hepatic ROS and a NASH-like phenotype with significant fibrosis. Plasma (ox)CoQ9 correlated with fibrosis progression. The mechanism of fibrosis may involve fructose inducing increased ROS associated with CD11b+F4/80+Gr1+ hepatic macrophage aggregation, resulting in transforming growth factor beta1-signaled collagen deposition and histologically visible hepatic fibrosis.
Hepatology 09/2010; 52(3):934-44. · 11.66 Impact Factor
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Journal of pediatric gastroenterology and nutrition 02/2010; 50(4):453-6. · 2.18 Impact Factor
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Christine Carter-Kent,
Lisa M Yerian,
Elizabeth M Brunt,
Paul Angulo, Rohit Kohli,
Simon C Ling,
Stavra A Xanthakos,
Peter F Whitington,
Phunchai Charatcharoenwitthaya,
Jason Yap,
Rocio Lopez,
Arthur J McCullough,
Ariel E Feldstein
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ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) may have distinct histological features in children and adults, but to date limited data are available on the spectrum and significance of histological lesions in pediatric patients. We conducted a multicenter study of children with well-characterized, biopsy-proven NAFLD to (1) assess the presence and significance of a constellation of histological lesions and (2) identify clinical and laboratory predictors of disease severity. One hundred thirty children with NAFLD seen from 1995 to 2007 in five centers in the United States and Canada were studied. Clinical and laboratory data were collected. Slides stained with hematoxylin-eosin and trichrome were evaluated by two liver pathologists. The NAFLD activity score (NAS) and the pattern of liver injury (type 1 or adult versus type 2 or pediatric nonalcoholic steatohepatitis [NASH]) were recorded. Fibrosis was staged using a published 7-point scale. The median age was 12 years (range, 4-18 years); 63% were boys, and 52% were Caucasian. Fibrosis was present in 87% of patients; of these, stage 3 (bridging fibrosis) was present in 20%. No patient had cirrhosis. The median NAS was 4. Overlapping features of both type 1 (adult pattern) and type 2 (pediatric pattern) NASH were found in 82% of patients. Compared with patients with no or mild fibrosis, those with significant fibrosis were more likely to have higher lobular and portal inflammation scores (P < 0.01), perisinusoidal fibrosis (P < 0.001), and NAS > or =5 (P < 0.005). Serum aspartate aminotransferase levels were the only clinical or laboratory data that independently predicted severity of fibrosis (P = 0.003). CONCLUSION: Our results highlight the limitations of published proposals to classify pediatric NAFLD, and identified histological lesions associated with progressive disease.
Hepatology 06/2009; 50(4):1113-20. · 11.66 Impact Factor
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ABSTRACT: Abnormal dietary intake of macronutrients is implicated in the development of obesity and fatty liver disease. Steatosis develops in cultured hepatocytes exposed to medium containing either a high concentration of long chain free fatty acids (HFFA) or medium deficient in methionine and choline (MCD). This study examined the mitochondrial reactive oxygen species (ROS)-dependent regulation of the phosphoinositol (PI) 3-kinase pathway in steatosis induced by exposure of AML-12 mouse hepatocytes to MCD or HFFA medium. Exposure to either MCD or HFFA medium resulted in increased production of superoxide anions and H(2)O(2), transduction of the PI 3-kinase pathway and steatosis. Inhibition of PI 3-kinase with LY294002 prevented steatosis. Pharmacologically inhibiting electron transport chain complex III production of ROS prevented activation of PI 3-kinase during macronutrient perturbation, whereas pharmacologically promoting electron transport chain complex III ROS production activated PI 3-kinase independent of nutrient input. The data suggest that H(2)O(2) is the ROS species involved in signal transduction; promoting the rapid conversion of superoxide to H(2)O(2) does not inhibit PI 3-kinase pathway activation during nutrient perturbation, and exogenous H(2)O(2) activates it independent of nutrient input. In addition to transducing PI 3-kinase, the ROS-dependent signal cascade amplifies the PI 3-kinase signal by maintaining phosphatase and tensin homolog in its inactive phosphorylated state. Knockdown of phosphatase and tensin homolog by small interfering RNA independently activated the PI 3-kinase pathway. Our findings suggest a common path for response to altered nutrition involving mitochondrial ROS-dependent PI 3-kinase pathway regulation, leading to steatosis.
Journal of Biological Chemistry 08/2007; 282(29):21327-36. · 4.77 Impact Factor
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ABSTRACT: Feeding mice a methionine and choline-deficient (MCD) diet serves as an experimental animal model for nonalcoholic steatohepatitis (NASH). In the present study we examined the effect of exposing AML-12 hepatocytes to MCD culture medium in regard to mechanisms of steatosis and alanine amino-transferase (ALT) release. Cells exposed to MCD medium developed significant and progressive steatosis from 6 to 24 h and also had significantly increased loss of ALT into the medium at 18 and 24 hours of incubation. No increased oxidative injury or cell death was observed. Osteopontin (OPN) mRNA in cells and protein expression in medium were significantly increased during 6-24 hours of incubation. MCD medium treatment also resulted in activation of PI3-kinase by 30 minutes and its downstream target p-Akt within 1hour of incubation. Steatosis was associated with increased expression of microsomal triglyceride transfer protein (MTTP) mRNA and increased ALT release with over expression of ALT mRNA, all of which were completely prevented by inhibition of PI3-kinase (LY294002). Blocking OPN signaling by treating with anti-OPN or anti-beta3-integrin antibody prevented the increased ALT release while only partially prevented the increased ALT mRNA expression, but had no effect on either steatosis or MTTP expression. In conclusion, incubation of cultured hepatocytes with MCD medium results in cellular steatosis and OPN dependent ALT release. PI3-kinase plays a central role in signaling the MCD medium-induced steatosis and increased OPN expression, whereas OPN appears to play a role in signaling hepatocyte ALT release but not steatosis.
AJP Gastrointestinal and Liver Physiology 08/2006; 291(1):G55-62. · 3.43 Impact Factor
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ABSTRACT: Cerebral ischemic insults disrupt normal respiratory activity in mitochondria. Carnitine plays an essential role in mitochondrial metabolism and in modulating excess acyl-coenzyme A (acyl-CoA) levels. The effects of cerebral ischemia on carnitine metabolism are not well understood, although the newborn may be particularly vulnerable to carnitine deficiency. We used a newborn rat model of hypoxia-ischemia (HI) to test the hypothesis that HI alters acyl-CoA:CoA homeostasis and that this effect can be prevented by treatment with carnitine.
A total of 120 postnatal day 7 rats were subjected to 70 minutes of HI after treatment with 16 mmol/kg intraperitoneal l-carnitine or diluent. Carnitine, acylcarnitines, and excitatory amino acids were measured by mass spectrometry, and carnitine acetyl transferase activity, superoxide, and levels of the mitochondrial phospholipid cardiolipin (CL) were measured at 2- and 24-hour recovery.
HI and hypoxia were associated with a significant increase in the ratio of acyl-CoA:CoA, which was prevented by treatment with carnitine. Carnitine treatment also prevented increases in glutamate, glycine, superoxide, and decrease of CL.
Carnitine metabolic pathways are compromised in HI and hypoxia. The protective effect of carnitine treatment on HI injury may be attributable to maintaining mitochondrial function.
Stroke 03/2006; 37(2):524-30. · 5.73 Impact Factor
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Journal of Pediatric Gastroenterology and Nutrition 11/2005; 41(4):479-82. · 2.30 Impact Factor
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Journal of Pediatric Gastroenterology and Nutrition 08/2005; 41(1):121-4. · 2.30 Impact Factor
