Lipidomic QTL in Diversity Outbred mice identifies a novel function for α/ß hydrolase domain 2 (Abhd2) as an enzyme that metabolizes phosphatidylcholine and cardiolipin.

We and others have previously shown that genetic association can be used to make causal connections between gene loci and small molecules measured by mass spectrometry in the bloodstream and in tissues. We identified a locus on mouse chromosome 7 where several phospholipids in liver showed strong genetic association to distinct gene loci. In this study, we integrated gene expression data with genetic association data to identify a single gene at the chromosome 7 locus as the driver of the phospholipid phenotypes. The gene encodes α/ß-hydrolase domain 2 (Abhd2), one of 23 members of the ABHD gene family. We validated this observation by measuring lipids in a mouse with a whole-body deletion of Abhd2. The Abhd2KO mice had a significant increase in liver levels of phosphatidylcholine and phosphatidylethanolamine. Unexpectedly, we also found a decrease in two key mitochondrial lipids, cardiolipin and phosphatidylglycerol, in male Abhd2KO mice. These data suggest that Abhd2 plays a role in the synthesis, turnover, or remodeling of liver phospholipids.

The Lard Works in Mysterious Ways: Ceramides in Nutrition-Linked Chronic Disease.

Diet influences onset, progression, and severity of several chronic diseases, including heart failure, diabetes, steatohepatitis, and a subset of cancers. The prevalence and clinical burden of these obesity-linked diseases has risen over the past two decades. These metabolic disorders are driven by ectopic lipid deposition in tissues not suited for fat storage, leading to lipotoxic disruption of cell function and survival. Sphingolipids such as ceramides are among the most deleterious and bioactive metabolites that accrue, as they participate in selective insulin resistance, dyslipidemia, oxidative stress and apoptosis. This review discusses our current understanding of biochemical pathways controlling ceramide synthesis, production and action; influences of diet on ceramide levels; application of circulating ceramides as clinical biomarkers of metabolic disease; and molecular mechanisms linking ceramides to altered metabolism and survival of cells. Development of nutritional or pharmacological strategies to lower ceramides could have therapeutic value in a wide range of prevalent diseases.

Adiponectin overexpression improves metabolic abnormalities caused by acid ceramidase deficiency but does not prolong lifespan in a mouse model of Farber Disease.

Farber Disease is a debilitating and lethal childhood disease of ceramide accumulation caused by acid ceramidase deficiency. The potent induction of a ligand-gated neutral ceramidase activity promoted by adiponectin may provide sufficient lowering of ceramides to allow for the treatment of Farber Disease. In vitro, adiponectin or adiponectin receptor agonist treatments lowered total ceramide concentrations in human fibroblasts from a patient with Farber Disease. However, adiponectin overexpression in a Farber Disease mouse model did not improve lifespan or immune infiltration. Intriguingly, mice heterozygous for the Farber Disease mutation were more prone to glucose intolerance and insulin resistance when fed a high-fat diet, and adiponectin overexpression protected from these metabolic perturbations. These studies suggest that adiponectin evokes a ceramidase activity that is not reliant on the functional expression of acid ceramidase, but indicates that additional strategies are required to ameliorate outcomes of Farber Disease.

Lipidomic QTL in Diversity Outbred mice identifies a novel function for α/ß hydrolase domain 2 ( Abhd2 ) as an enzyme that metabolizes phosphatidylcholine and cardiolipin.

We and others have previously shown that genetic association can be used to make causal connections between gene loci and small molecules measured by mass spectrometry in the bloodstream and in tissues. We identified a locus on mouse chromosome 7 where several phospholipids in liver showed strong genetic association to distinct gene loci. In this study, we integrated gene expression data with genetic association data to identify a single gene at the chromosome 7 locus as the driver of the phospholipid phenotypes. The gene encodes α/ß-hydrolase domain 2 ( Abhd2 ), one of 23 members of the ABHD gene family. We validated this observation by measuring lipids in a mouse with a whole-body deletion of Abhd2 . The Abhd2 KO mice had a significant increase in liver levels of phosphatidylcholine and phosphatidylethanolamine. Unexpectedly, we also found a decrease in two key mitochondrial lipids, cardiolipin and phosphatidylglycerol, in male Abhd2 KO mice. These data suggest that Abhd2 plays a role in the synthesis, turnover, or remodeling of liver phospholipids.

Carnitine deficiency among hospitalized pediatric patients: A retrospective study of critically ill patients receiving extracorporeal membrane oxygenation therapy.

BACKGROUND: The metabolic demands associated with critical illness place patients at risk for nutrition deficits. Carnitine is a small molecule essential for fatty acid oxidation and gluconeogenesis. Secondary carnitine deficiency can have clinically significant complications and has been observed anecdotally in patients receiving extracorporeal membrane oxygenation (ECMO) therapy at our institution. Guidelines for monitoring and supplementing carnitine are lacking. This retrospective study determined whether critically ill pediatric patients receiving ECMO have an increased risk of carnitine deficiency. METHODS: Acylcarnitine analysis was performed on residual specimens from patients who received ECMO therapy. The control data were a convenience sample gathered by chart review of patients who had been tested for carnitine during a hospitalization. RESULTS: Acylcarnitines were measured in 217 non-ECMO patients and 81 ECMO patients. Carnitine deficiency, based on age-specific reference ranges, was observed in 41% of ECMO cases compared with 21% of non-ECMO cases. Multivariable analysis of age-matched patients identified that the odds of carnitine deficiency were significantly lower among patients on the floor compared with ECMO patients (odds ratio, 0.21; 95% CI, 0.10-0.44). Age-specific frequency of qualitative carnitine deficiency ranged from 15% (patients >5 years old) to 56% (patients 1 week to 1 month old) in ECMO patients and 15% (patients >5 years old) to 34% (patients 1-5 years old) in non-ECMO patients. CONCLUSION: In this study, ECMO patients were carnitine deficient more frequently compared with other inpatients, with the highest rates of deficiency among ECMO patients between 1 week and 1 month old.

Tutorial: Triheptanoin and Nutrition Management for Treatment of Long-Chain Fatty Acid Oxidation Disorders.

BACKGROUND: Patients with severe long-chain fatty acid oxidation disorders (LC-FAODs) experience serious morbidity and mortality despite traditional dietary management including medium-chain triglyceride (MCT)-supplemented, low-fat diets. Triheptanoin is a triglyceride oil that is broken down to acetyl-coenzyme A (CoA) and propionyl-CoA, which replenishes deficient tricarboxylic acid cycle intermediates. We report the complex medical and nutrition management of triheptanoin therapy initiated emergently for 3 patients with LC-FAOD. METHODS: Triheptanoin (Ultragenyx Pharmaceutical, Inc, Novato, CA, USA) was administered to 3 patients with LC-FAOD on a compassionate-use basis. Triheptanoin was mixed with non-MCT-containing low-fat formula. Patients were closely followed with regular cardiac and laboratory monitoring. RESULTS: Cardiac ejection fraction normalized after triheptanoin initiation. Patients experienced fewer hospitalizations related to metabolic crises while on triheptanoin. Patient 1 has tolerated oral administration without difficulty since birth. Patients 2 and 3 experienced increased diarrhea. Recurrent breakdown of the silicone gastrostomy tube occurred in patient 3, whereas the polyurethane nasogastric tube for patient 2 remained intact. Patient 3 experiences recurrent episodes of elevated creatine kinase levels and muscle weakness associated with illness. Patient 3 had chronically elevated C10-acylcarnitines while on MCT supplementation, which normalized after initiation of triheptanoin and discontinuation of MCT oil. CONCLUSIONS: Triheptanoin can ameliorate acute cardiomyopathy and increase survival in patients with severe LC-FAOD. Substituting triheptanoin for traditional MCT-based treatment improves clinical outcomes. MCT oil might be less effective in carnitine-acylcarnitine translocase deficiency patients compared with other FAODs and needs further investigation.

Fatty acid oxidation disorders.

Fatty acid oxidation disorders (FAODs) are inborn errors of metabolism due to disruption of either mitochondrial ß-oxidation or the fatty acid transport using the carnitine transport pathway. The presentation of a FAOD will depend upon the specific disorder, but common elements may be seen, and ultimately require a similar treatment. Initial presentations of the FAODs in the neonatal period with severe symptoms include cardiomyopathy, while during infancy and childhood liver dysfunction and hypoketotic hypoglycemia are common. Episodic rhabdomyolysis is frequently the initial presentation during or after adolescence; although, these symptoms may develop at any age for most of the FAODs The treatment of all FAOD's include avoidance of fasting, aggressive treatment during illness, and supplementation of carnitine, if necessary. The long-chain FAODs differ by requiring a fat-restricted diet and supplementation of medium chain triglyceride oil and often docosahexaenoic acid (DHA)-an essential fatty acid, crucial for brain, visual, and immune functions and prevention of fat soluble vitamin deficiencies. The FAOD are a group of autosomal recessive disorders associated with significant morbidity and mortality, but early diagnosis on newborn screening (NBS) and early initiation of treatment are improving outcomes. There is a need for clinical studies including randomized, controlled, therapeutic trials to continue to evaluate current understanding and to implement future therapies.

Organic acid disorders.

Organic acids (OAs) are intermediary products of several amino acid catabolism or degradation via multiple biochemical pathways for energy production. Vitamins or co-factors are often quintessential elements in such degradation pathways and OA metabolism. OAs that result from enzyme defects in these pathways can be identified in body fluids utilizing gas chromatography-mass spectrometry techniques (GC/MS). OAs are silent contributor to acid base imbalance and can affect nitrogen balance and recycling. Since OA production occurs in distal steps of a specific amino acid catabolism, offending amino acid accumulation is not characteristic. OA disorders as inborn errors of metabolism (IEM) are included in differential diagnosis of metabolic acidosis, as the common mnemonic MUDPILES taught in medical schools. High anion gap metabolic acidosis with hyperammonemia is a characteristic OA biochemical finding. VOMIT (valine, odd chain fatty acids, methionine, isoleucine, and threonine) is a smart acronym and a common clinical presentation of OA disorders and can present as early life-threatening illness, prior to Newborn Screening results availability. Easy identification and available medical formula make the field of metabolic nutrition vital for management of OA disorders. Treatment strategies also involve cofactor/vitamin utilization to aid specific pathways and disorder management. Optimal metabolic control and regular monitoring is key to long-term management and prevention of morbidity, disability and mortality. Prompt utilization of acute illness protocol (AIP) or emergency protocol and disorder specific education of family members or caregivers, primary care physicians and local emergency health care facilities; cautiously addressing common childhood illnesses in patients with OA disorders, can help avoid poor short- and long-term morbidity, disability and mortality outcomes.