Following the discovery of LC-FAODs, it was generally assumed that supplementation for these patients with MCT oil would prevent clinical symptoms, as the even-chain fats it contained could completely bypass the metabolism. However, clinical symptoms persisted in patients, and is now recognized to be due at least in part to depletion of odd-chain TCA cycle intermediates and subsequent persistent energy deficiency.
In recognition of this deficit, triheptanoin, a food-grade supplemental heptanoyl-triglyceride, was proposed as a more physiologically balanced MCT as 2 cycles of FAO produced both 2- and 3-carbon intermediates. Early case reports on efficacy led to a significant compassionate-use experience with the medication. Two retrospective studies demonstrated considerable improvement in treated patients, specifically reductions in episodes and hospital days related to hypoglycemia, cardiomyopathy, and rhabdomyolysis.
Triheptanoin is available commercially as an oral liquid supplied in a mL bottle supplying 8. As with other medium-chain fats, heptanoate can diffuse across the mitochondrial membrane and be metabolized by the medium-chain—specific enzymes of FAO, bypassing the need for the carnitine cycle, the long-chain transport, and long-chain—specific enzymes.
The first was a double-blinded, randomized controlled study that compared changes in physiologic function after treatment with pharmaceutically pure octanoyl or heptanoylglycerol in a double-blind fashion in 32 participants.
Patients in the C7 triheptanoin group experienced increased left ventricular LV ejection fraction by 7. There were no significant differences in adverse effects AEs between C7 and C8, and the majority were minor and gastrointestinal in nature.
The improvement in cardiac function in hearts with no obvious dysfunction is in keeping with improved cardiac outcomes in other clinical trials, whereas the lack of a difference in clinical outcomes reflects the short duration of the study and the relative stability of patients entering the study. Hospitalization event rates, number of hospitalization days per year, and event rates for rhabdomyolysis, hypoglycemia, and cardiomyopathy were collected and compared before and after triheptanoin initiation Table A total of hospitalizations were documented for 20 subjects from birth through the end of the study period.
Additionally, hypoglycemia events were nearly eliminated with a significant reduction in events per year and hospital days per year. Rhabdomyolysis events and hospitalization days trended down but were non-significantly changed with addition of triheptanoin. The data collected related to cardiomyopathy symptoms were insufficient to assess for impact of triheptanoin administration. Results of a study for FDA registration of triheptanoin have also been published.
Patients acted as their own control. The incidence of and hospitalizations related to hypoglycemia, cardiomyopathy, and rhabdomyolysis were captured and compared with the year prior to starting in the study. Twenty-nine patients 0. The composite end points of annualized event rate and annualized duration rate for all events were significantly reduced as noted in Table 5. AEs were often managed with smaller, frequent doses mixed with food.
Subsequently, 75 patients from previous studies were enrolled in a long-term safety extension and efficacy open-label phase 2 study. Patients will begin or continue treatment with triheptanoin while maintaining other dietary restrictions.
Primary outcome measures of this study include annualized LC-FAOD major clinical events rhabdomyolysis, hypoglycemia, and cardiomyopathy through 84 months on treatment and monitoring for number of treatment-emergent AEs or serious AEs.
This study is underway with an estimated completion date of September The peroxisome proliferator-activated receptors PPARs are members of the nuclear receptor superfamily, ligand-modulated transcription factors that regulate gene expression of many cellular processes.
The first trial, which was an open-label, 6-month pilot study with a 3-year extension, showed increased level of whole-body fat oxidation, improved QOL scores, reduced creatinine kinase levels, and diminished occurrence of rhabdomyolysis with bezafibrate. The primary outcome measure of the study is to assess the safety and tolerability of REN LC-FAODs are a heterogeneous group of disorders that have seen some improvement in clinical outcomes through early identification of patients with NBS but remain problematic, nonetheless.
The recent FDA approval of triheptanoin is likely to improve—but not eliminate—these clinical problems. Available clinical studies demonstrate that triheptanoin directly addresses TCA cycle deficiencies that arise in LC-FAODs and improves clinical outcomes with reduction in clinical symptoms and hospital days.
As such, triheptanoin represents a substantial breakthrough that will greatly improve the treatment and management of LC-FAODs. Funding source: This activity is supported by an educational grant from Ultragenyx Pharmaceutical Inc. Author disclosure : Dr Vockley has the following relevant financial relationships with commercial interests to disclose:. Authorship information: Substantial contributions to the concept and design; analysis and interpretation of data; and critical revision of the manuscript for important intellectual content.
Carnitine transport and fatty acid oxidation. Biochim Biophys Acta. Orphan drugs in development for long-chain fatty acid oxidation disorders: challenges and progress. Orphan Drugs: Res Rev. Healthy fatty acid oxidation. Several enzymes help break down fats so that they may be turned into energy.
Children who have one of these disorders are missing or have a deficiency of the enzymes needed to break down metabolize fats. The lack of these enzymes leaves the body short of energy and allows breakdown products, such as acyl-CoA, to accumulate. The enzyme most commonly deficient is medium-chain acyl-CoA dehydrogenase Medium-chain acyl-CoA dehydrogenase MCAD deficiency Fatty acid oxidation disorders are lipid metabolism disorders that are caused by a lack or deficiency of the enzymes needed to break down fats, resulting in delayed mental and physical development Other enzyme deficiencies include short-chain acyl-CoA dehydrogenase SCAD deficiency, long-chain 3-hydroxyacyl-CoA dehydrogenase LCHAD deficiency Long-chain 3-hydroxyacyl-CoA dehydrogenase LCHAD deficiency Fatty acid oxidation disorders are lipid metabolism disorders that are caused by a lack or deficiency of the enzymes needed to break down fats, resulting in delayed mental and physical development Most of these disorders begin in infancy.
Treatment of fatty acid oxidation disorders varies depending on the type of fatty substances that accumulate in the blood and tissues. This disorder is one of the most common inherited disorders of metabolism, particularly among people of Northern European descent. Symptoms of MCAD deficiency usually develop after 2 to 3 months of age. Children are most likely to develop symptoms if they go without food for a period of time which depletes other sources of energy or have an increased need for calories because of exercise or illness.
The level of sugar glucose in the blood drops significantly hypoglycemia , causing confusion or coma. Children become weak and may have vomiting or seizures. Over the long term, children have delayed mental and physical development, an enlarged liver, heart muscle weakness, and an irregular heartbeat. Sudden death may occur. Since , nearly every state in the United States has required that all newborns be screened for MCAD deficiency with a blood test.
Tests of the urine and other tissues may also be done. Complete oxidation of one palmitate molecule fatty acid containing 16 carbons generates ATP molecules. Download a PDF version of the fatty acid beta-oxidation pathway. Cancer metabolism poster. Pyruvate dehydrogenase PDH. To allow FAO completion, a coordinate network of enzymes and transport proteins is required.
The first component of this system is the carnitine palmitoyltransferase 1 CPT1 responsible for transfer acyl moieties to carnitine. Several studies indicated that the stimulation of CPT1 activity and expression has a protective effect against renal fibrosis.
Therefore, the network of enzymes and transporters linked to FAO may represent potential pharmacological targets deserving further attention in the development of new drugs to attenuate renal dysfunction.
The kidney is one of the most energy-demanding organs in the human body, as demonstrated by Elia Elia, in a study performed in describing the specific resting metabolic rates of major organs and tissues in adults. The following values expressed as in kcal kg —1 d —1 were indeed calculated: for liver, for brain, for heart and kidneys, 13 for skeletal muscle, 4.
Accordingly, the kidney is second only to the heart in terms of mitochondrial abundance Pagliarini et al. This scenario correlates well with the high request of ATP by the kidney to remove waste from the blood, to reabsorb nutrients, to modulate the balance of electrolytes and fluid, to maintain the acid-base homeostasis, and to regulate the blood pressure Bhargava and Schnellmann, Podocytes, endothelial and mesangial cells first use glucose to produce ATP for basal cell processes Forbes, These cells are completely dependent on the oxidative phosphorylation, i.
Indeed, the efficiency of ATP production from palmitate is higher than that from glucose. Another reason to avoid glycolysis for producing ATP is that proximal tubules harbor a high glucose concentration gradient from their luminal urinary filtrate to basal blood side for glucose reabsorption. Hence, using glucose to derive energy could be toxic, especially under conditions of metabolic imbalance such as in diabetes Forbes, In this minireview, the network of transporters and enzymes responsible for the mitochondrial fatty acid oxidation will be dealt with focusing on derangements that underlie kidney injury with special reference to the Acute Kidney Disease AKI.
Fatty acid oxidation mainly occurs in mitochondria and involves a repeated sequence of reactions that result in the conversion of fatty acids to acetyl-CoA. Fatty acids are mainly taken up by proximal tubule cells through CD Alternatively, fatty acids result from the deacylation of cellular phospholipids mediated by phospholipase A2 PLA2. Independently from their origin, fatty acids are then activated in the cytosol by the long-chain acyl-CoA synthetase producing long-chain acyl-CoA.
Due to the lack of an acyl-CoA transporter in the mitochondrial inner membrane, the acyl group is transferred to the shuttle molecule carnitine for translocation into the matrix Indiveri et al. The shuttling process starts with the action of CPT1 that catalyzes the conversion of acyl-CoAs into acylcarnitines Figure 1. CPT1 was identified as part of a large protein complex of the mitochondrial outer membrane, protruding toward the cytosol, which includes long-chain acyl-CoA synthetase ACSL and the voltage-dependent anion channel VDAC also known as porin Lee et al.
The formed acylcarnitines cross the inner mitochondrial membrane through the action of the carnitine acylcarnitine carrier CAC — SLC25A This transporter mediates an antiport reaction coupling the entry of acylcarnitine into the matrix with the exit of free carnitine Figure 1. It exhibits a higher affinity for acylcarnitines with longer carbon chains and is located in the inner mitochondrial membrane where takes contact with CPT2 located on the matrix side of the inner mitochondrial membrane Lee et al.
Five types of ACADs are known which are classified according to the substrate specificity; hence, each isoform has a preference for substrates with different chain lengths. These redox enzymes use FAD as a cofactor. The electrons from FADH 2 are subsequently transferred to the electron transferring factor ETF , which in turn releases the electrons to the ETF dehydrogenase coupled with the electron transport chain via the Coenzyme Q. As above described, the availability of carnitine for fatty acid transport into mitochondria is crucial for the accomplishment of FAO.
Due to its fundamental role, it is not surprising that the carnitine homeostasis is strictly regulated Pochini et al. The endogenous carnitine synthesis is insufficient to meet the human body need, thus, about half of the carnitine pool is absorbed from the diet.
The transporter also plays a major role in the renal tubular reabsorption of carnitine which concurs in maintaining the homeostasis Pochini et al. Kidney diseases are associated to some extent with carnitine homeostasis derangements. Indeed, some patients with kidney diseases develop carnitine deficiency Hedayati, Figure 1. The picture represents a sketch of renal proximal tubule cells. Fatty acids FA enter the cytosol via CD The link between lipid accumulation and kidney disease was suggested for the first time in by Rudolf Virchow.
Lipid accumulation reflects an imbalance between fatty acid utilization and fatty acid supply. Since triglycerides buffer fatty acid excess, the overload is often visible as lipid droplets. Several studies suggested that glomeruli and proximal tubules are the most susceptible to lipid accumulation and hence linked to kidney dysfunction Figure 2 ; Bobulescu, The molecular features of DN are not yet completely understood; however, lipotoxicity caused by fatty acid deposition and tubule-interstitial fibrosis characterized by epithelial-to-mesenchymal transition EMT , seem to be hallmarks of DN.
Interestingly, a study conducted on human proximal tubular cells, cultured in high glucose medium to mimic diabetic condition, shed light on the events underlying DN onset. It seems that the lipotoxicity occurs before the EMT Xu et al. Another pathological condition characterized by fatty acid accumulation causing lipotoxicity is one of the most common forms of acute kidney injury AKI , which is the ischemic renal injury IRI.
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