Abstract 412: DJ-1 Deficiency Impairs Post-Ischemic Cardiac Fatty Acid Oxidation

Background: DJ-1 is a cytoprotective protein implicated in many cellular processes. We have recently shown that DJ-1 plays a protective role in the setting of acute myocardial ischemia-reperfusion injury and heart failure. However, specific mechanisms of action remain unknown. Here, we sought to determine if DJ-1 maintains fatty acid oxidation following myocardial I/R injury via the regulation of PPARalpha transcriptional activity. Methods and Results: WT and DJ-1 KO hearts were subjected to 45 minutes of ischemia via coronary artery ligation followed by up to 72 hours of reperfusion. Initial studies revealed that PPARalpha activity (PPARalpha Transcription Factor Assay Kit; abcam) was lower in DJ-1 KO hearts under both basal (sham) and I/R conditions. Next, we performed an analysis of PPAR genes using a qPCR array (Mouse PPAR Targets RT2 Profiler PCR Array from Qiagen) that profiled the expression of 84 key genes involved in PPAR activation and response. Marked differences in genes involved in FA metabolism were evident in the hearts of DJ-1 KO mice. Further studies using qPCR validated a significant decrease in the expression of acsl1 (protein ACSL1), acsl3, acsl5, cpt1b (protein CPT1), slc25a20 (protein CACT), and cpt2. The protein expression of ACSL1, CPT1, and CACT were also decreased in the hearts of DJ-1 KO mice following I/R injury. These changes were accompanied by higher cardiac lipid content and depressed mitochondrial fatty-acid β-oxidation and ATP synthesis. Conclusion: These data demonstrate that DJ-1 plays an essential role in regulating post-I/R cardiac FAO. Future studies will garner mechanistic insight for the impaired function of PPARalpha with the loss of DJ-1.

Download Full-text

3,5-Diiodo-l-thyronine rapidly enhances mitochondrial fatty acid oxidation rate and thermogenesis in rat skeletal muscle: AMP-activated protein kinase involvement

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.90642.2008 ◽

2009 ◽

Vol 296 (3) ◽

pp. E497-E502 ◽

Cited By ~ 57

Author(s):

A. Lombardi ◽

P. de Lange ◽

E. Silvestri ◽

R. A. Busiello ◽

A. Lanni ◽

...

Keyword(s):

Skeletal Muscle ◽

Fatty Acids ◽

Fatty Acid ◽

Energy Metabolism ◽

Fatty Acid Oxidation ◽

Atp Synthesis ◽

Acid Oxidation ◽

Mitochondrial Fatty Acid Oxidation ◽

Mitochondrial Fatty Acid ◽

Amp Activated Protein Kinase

Triiodothyronine regulates energy metabolism and thermogenesis. Among triiodothyronine derivatives, 3,5-diiodo-l-thyronine (T2) has been shown to exert marked effects on energy metabolism by acting mainly at the mitochondrial level. Here we investigated the capacity of T2 to affect both skeletal muscle mitochondrial substrate oxidation and thermogenesis within 1 h after its injection into hypothyroid rats. Administration of T2 induced an increase in mitochondrial oxidation when palmitoyl-CoA (+104%), palmitoylcarnitine (+80%), or succinate (+30%) was used as substrate, but it had no effect when pyruvate was used. T2 was able to 1) activate the AMPK-ACC-malonyl-CoA metabolic signaling pathway known to direct lipid partitioning toward oxidation and 2) increase the importing of fatty acids into the mitochondrion. These results suggest that T2 stimulates mitochondrial fatty acid oxidation by activating several metabolic pathways, such as the fatty acid import/β-oxidation cycle/FADH2-linked respiratory pathways, where fatty acids are imported. T2 also enhanced skeletal muscle mitochondrial thermogenesis by activating pathways involved in the dissipation of the proton-motive force not associated with ATP synthesis (“proton leak”), the effect being dependent on the presence of free fatty acids inside mitochondria. We conclude that skeletal muscle is a target for T2, and we propose that, by activating processes able to enhance mitochondrial fatty acid oxidation and thermogenesis, T2 could play a role in protecting skeletal muscle against excessive intramyocellular lipid storage, possibly allowing it to avoid functional disorders.

Download Full-text

Impaired mitochondrial fatty acid oxidation and insulin resistance in aging: novel protective role of glutathione

Aging Cell ◽

10.1111/acel.12073 ◽

2013 ◽

Vol 12 (3) ◽

pp. 415-425 ◽

Cited By ~ 38

Author(s):

Dan Nguyen ◽

Susan L. Samson ◽

Vasumathi T. Reddy ◽

Erica V. Gonzalez ◽

Rajagopal V. Sekhar

Keyword(s):

Insulin Resistance ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Protective Role ◽

Acid Oxidation ◽

Mitochondrial Fatty Acid Oxidation ◽

Mitochondrial Fatty Acid

Download Full-text

The transcriptional coactivator PGC-1α is essential for maximal and efficient cardiac mitochondrial fatty acid oxidation and lipid homeostasis

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00081.2008 ◽

2008 ◽

Vol 295 (1) ◽

pp. H185-H196 ◽

Cited By ~ 117

Author(s):

John J. Lehman ◽

Sihem Boudina ◽

Natasha Hausler Banke ◽

Nandakumar Sambandam ◽

Xianlin Han ◽

...

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Atp Synthesis ◽

Lipid Homeostasis ◽

Acid Oxidation ◽

Metabolic Efficiency ◽

Transcriptional Coactivator ◽

Mitochondrial Fatty Acid Oxidation ◽

Mitochondrial Fatty Acid ◽

Myocardial Fibers

High-capacity mitochondrial ATP production is essential for normal function of the adult heart, and evidence is emerging that mitochondrial derangements occur in common myocardial diseases. Previous overexpression studies have shown that the inducible transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α is capable of activating postnatal cardiac myocyte mitochondrial biogenesis. Recently, we generated mice deficient in PGC-1α (PGC-1α−/− mice), which survive with modestly blunted postnatal cardiac growth. To determine if PGC-1α is essential for normal cardiac energy metabolic capacity, mitochondrial function experiments were performed on saponin-permeabilized myocardial fibers from PGC-1α−/− mice. These experiments demonstrated reduced maximal (state 3) palmitoyl-l-carnitine respiration and increased maximal (state 3) pyruvate respiration in PGC-1α−/− mice compared with PGC-1α+/+ controls. ATP synthesis rates obtained during maximal (state 3) respiration in permeabilized myocardial fibers were reduced for PGC-1α−/− mice, whereas ATP produced per oxygen consumed (ATP/O), a measure of metabolic efficiency, was decreased by 58% for PGC-1α−/− fibers. Ex vivo isolated working heart experiments demonstrated that PGC-1α−/− mice exhibited lower cardiac power, reduced palmitate oxidation, and increased reliance on glucose oxidation, with the latter likely a compensatory response. 13C NMR revealed that hearts from PGC-1α−/− mice exhibited a limited capacity to recruit triglyceride as a source for lipid oxidation during β-adrenergic challenge. Consistent with reduced mitochondrial fatty acid oxidative enzyme gene expression, the total triglyceride content was greater in hearts of PGC-1α−/− mice relative to PGC-1α+/+ following a fast. Overall, these results demonstrate that PGC-1α is essential for the maintenance of maximal, efficient cardiac mitochondrial fatty acid oxidation, ATP synthesis, and myocardial lipid homeostasis.

Download Full-text

Abstract 1600: Endogenous Nox4 Is Protective During Ischemia/reperfusion In The Heart

Circulation ◽

10.1161/circ.118.suppl_18.s_355 ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Tetsuro Ago ◽

Junya Kuroda ◽

Chiao-Po Hsu ◽

Peiyong Zhai ◽

Jayashree Pain ◽

...

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Ischemia Reperfusion ◽

Luciferase Assay ◽

Acid Oxidation ◽

Ros Generation ◽

Peroxisome Proliferator ◽

Area At Risk ◽

Mitochondrial Fatty Acid Oxidation ◽

Mitochondrial Fatty Acid

Although excessive production of reactive oxygen species (ROS) causes cellular injuries, ROS also act as signaling molecules and regulate physiological cellular functions. ROS are extensively generated during ischemia/reperfusion (I/R) and cause tissue damages. The NAD(P)H oxidases are major sources of ROS in the cardiovascular system. Among NAD(P)H oxidase proteins, Nox4 is expressed in the heart and cultured cardiac myocytes. To test whether ROS derived from Nox4 induce tissue damage following I/R in the heart, we made mice on FVB background with cardiac-specific overexpression of wild-type Nox4 (Tg-Nox4) and catalytically inactive Nox4 (Tg-DN-Nox4 (P437H)) in which NADPH is unable to bind to Nox4. We confirmed that ROS generation and oxidative stress in the heart are greater in Tg-Nox4 and is lower in Tg-DN-Nox4, compared with non-transgenic mice (NTg), as determined by dihydroethidium fluorescence and 8-hydroxyguanosine staining, respectively. Neither Tg-Nox4 nor Tg-DN-Nox4 exhibited obvious baseline phenotype at 3 months of age. Tg-Nox4, Tg-DN-Nox4, and NTg (n=5, each) at 3 months old were subjected to 45 minutes ischemia, by ligating the left anterior descending artery, followed by 24 hours reperfusion. Unexpectedly, myocardial infarction (MI) size/area at risk (AAR) determined by TTC staining was significantly greater in Tg-DN-Nox4 than in NTg (67% vs 30 %, p<0.05). On the other hand, MI size/AAR in Tg-Nox4 (35 %) was comparable to that in NTg. To elucidate the mechanism by which suppression of Nox4 deteriorates I/R injury, we examined expression of proteins involved in cardiac metabolism. We found that expression levels of peroxisome proliferator-activated receptor α (PPARα), an important transcription factor stimulating mitochondrial fatty acid oxidation, remained high in Tg-DN-Nox4 during I/R (3.0 fold vs NTg), whereas it was suppressed in NTg and Tg-Nox4. Consistently, overexpression of DN-Nox4 enhanced transcriptional activity of PPARα by 2-fold, as determined by a luciferase assay, in cultured myocytes. Taken together, endogenous Nox4 may protect the heart from I/R injury by suppressing fatty acid oxidation through downregulation of PPARα which would otherwise lead to excess ROS generation after I/R.

Download Full-text