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Impaired mitochondrial medium-chain fatty acid oxidation drives periportal macrovesicular steatosis in sirtuin-5 knockout mice.

ABSTRACT: Medium-chain triglycerides (MCT), containing C8-C12 fatty acids, are used to treat several pediatric disorders and are widely consumed as a nutritional supplement. Here, we investigated the role of the sirtuin deacylase Sirt5 in MCT metabolism by feeding Sirt5 knockout mice (Sirt5KO) high-fat diets containing either C8/C10 fatty acids or coconut oil, which is rich in C12, for five weeks. Coconut oil, but not C8/C10 feeding, induced periportal macrovesicular steatosis in Sirt5KO mice. 14C-C12 degradation was significantly reduced in Sirt5KO liver. This decrease was localized to the mitochondrial ?-oxidation pathway, as Sirt5KO mice exhibited no change in peroxisomal C12 ?-oxidation. Endoplasmic reticulum ?-oxidation, a minor fatty acid degradation pathway known to be stimulated by C12 accumulation, was increased in Sirt5KO liver. Mice lacking another mitochondrial C12 oxidation enzyme, long-chain acyl-CoA dehydrogenase (LCAD), also developed periportal macrovesicular steatosis when fed coconut oil, confirming that defective mitochondrial C12 oxidation is sufficient to induce the steatosis phenotype. Sirt5KO liver exhibited normal LCAD activity but reduced mitochondrial acyl-CoA synthetase activity with C12. These studies reveal a role for Sirt5 in regulating the hepatic response to MCT and may shed light into the pathogenesis of periportal steatosis, a hallmark of human pediatric non-alcoholic fatty liver disease.

SUBMITTER: Goetzman ES

PROVIDER: S-EPMC7591893 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Impaired mitochondrial medium-chain fatty acid oxidation drives periportal macrovesicular steatosis in sirtuin-5 knockout mice.

Goetzman Eric S ES Bharathi Sivakama S SS Zhang Yuxun Y Zhao Xue-Jun XJ Dobrowolski Steven F SF Peasley Kevin K Sims-Lucas Sunder S Monga Satdarshan P SP

Scientific reports 20201027 1

Medium-chain triglycerides (MCT), containing C8-C12 fatty acids, are used to treat several pediatric disorders and are widely consumed as a nutritional supplement. Here, we investigated the role of the sirtuin deacylase Sirt5 in MCT metabolism by feeding Sirt5 knockout mice (Sirt5KO) high-fat diets containing either C8/C10 fatty acids or coconut oil, which is rich in C12, for five weeks. Coconut oil, but not C8/C10 feed ...[more]

PMID: 33110171

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Project description:This study is aimed at determining the ability of computed tomography- (CT-) based radiomic analysis to distinguish between grade 0/1 and grade 2/3 macrovesicular steatosis (MaS) in cadaveric donor liver transplantation cases. Preoperative noncontrast-enhanced CT images of 150 patients with biopsy-confirmed MaS were analyzed retrospectively; these patients were classified into the low-grade MaS (n = 100, grade 0 or 1) and high-grade MaS (n = 50, grade 2 or 3) groups. Three-dimensional spherical regions of interest of 40 pixel (2.5 cm) in diameter were placed in the right anterior and left lateral segments of the liver. Thereafter, 300 regions of interest (ROIs) were segmented and randomly assigned to the training and testing groups at a ratio of 7 : 3. A total of 402 radiomic features were extracted from each ROI. For MaS classification, a radiomic model was established using multivariate logistic regression analysis. Clinical data, including age, sex, and liver function, were collected to establish the clinical model at the patient level. The performances of the radiomic and clinical models, i.e., the diagnostic discrimination, calibration, and clinical utilities, were evaluated. The radiomic model, with seven selected features, depicted a good discrimination with an area under the receiver operating characteristic curve (AUC) of 0.907 (95% confidence interval (CI): 0.869-0.940) in the training cohort and 0.906 (95% CI: 0.843-0.959) in the testing cohort. The calibration curve revealed good agreement between the predicted and observed probabilities in the training and testing cohorts (both P > 0.05 in the H-L test). Decision curve analysis revealed that the radiomic model was more beneficial than the treat-all or treat-none schemes for predicting the MaS grade. Alanine transaminase and gamma-glutamyl transferase were used for building the clinical model, and the AUC was 0.784 in the total cohort. The CT-based radiomic model outperforming the conventional clinical model could provide an important reference for MaS grading in cadaveric liver donors.

Project description:BackgroundBranched chain amino acids (BCAA) can impair insulin signaling, and cardiac insulin resistance can occur in the failing heart. We, therefore, determined if cardiac BCAA accumulation occurs in patients with dilated cardiomyopathy (DCM), due to an impaired catabolism of BCAA, and if stimulating cardiac BCAA oxidation can improve cardiac function in mice with heart failure.MethodFor human cohorts of DCM and control, both male and female patients of ages between 22 and 66 years were recruited with informed consent from University of Alberta hospital. Left ventricular biopsies were obtained at the time of transplantation. Control biopsies were obtained from non-transplanted donor hearts without heart disease history. To determine if stimulating BCAA catabolism could lessen the severity of heart failure, C57BL/6J mice subjected to a transverse aortic constriction (TAC) were treated between 1 to 4-week post-surgery with either vehicle or a stimulator of BCAA oxidation (BT2, 40 mg/kg/day).ResultEchocardiographic data showed a reduction in ejection fraction (54.3 ± 2.3 to 22.3 ± 2.2%) and an enhanced formation of cardiac fibrosis in DCM patients when compared to the control patients. Cardiac BCAA levels were dramatically elevated in left ventricular samples of patients with DCM. Hearts from DCM patients showed a blunted insulin signalling pathway, as indicated by an increase in P-IRS1ser636/639 and its upstream modulator P-p70S6K, but a decrease in its downstream modulators P-AKT ser473 and in P-GSK3β ser9. Cardiac BCAA oxidation in isolated working hearts was significantly enhanced by BT2, compared to vehicle, following either acute or chronic treatment. Treatment of TAC mice with BT2 significantly improved cardiac function in both sham and TAC mice (63.0 ± 1.8 and 56.9 ± 3.8% ejection fraction respectively). Furthermore, P-BCKDH and BCKDK expression was significantly decreased in the BT2 treated groups.ConclusionWe conclude that impaired cardiac BCAA catabolism and insulin signaling occur in human heart failure, while enhancing BCAA oxidation can improve cardiac function in the failing mouse heart.

Dataset Information

Impaired mitochondrial medium-chain fatty acid oxidation drives periportal macrovesicular steatosis in sirtuin-5 knockout mice.

Publications

Impaired mitochondrial medium-chain fatty acid oxidation drives periportal macrovesicular steatosis in sirtuin-5 knockout mice.

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