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 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.

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.

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.

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.