Myristate-derived d16:0 sphingolipids constitute a cardiac sphingolipid pool with distinct synthetic routes and functional properties.

BACKGROUND: Myristate is a novel potential substrate for sphingoid base synthesis. RESULTS: Myocardial sphingoid base synthesis utilizes myristate; these sphingolipids are functionally non-redundant with canonical sphingoid bases. CONCLUSION: d16:0 and d16:1 sphingolipids constitute an appreciable proportion of cardiac dihydrosphingosine and dihydroceramide, with distinct biological roles. SIGNIFICANCE: This pool of sphingolipids may play a heretofore unsuspected role in myocardial pathology or protection. The enzyme serine palmitoyltransferase (SPT) catalyzes the formation of the sphingoid base "backbone" from which all sphingolipids are derived. Previous studies have shown that inhibition of SPT ameliorates pathological cardiac outcomes in models of lipid overload, but the metabolites responsible for these phenotypes remain unidentified. Recent in vitro studies have shown that incorporation of the novel subunit SPTLC3 broadens the substrate specificity of SPT, allowing utilization of myristoyl-coenzyme A (CoA) in addition to its canonical substrate palmitoyl-CoA. However, the relevance of these findings in vivo has yet to be determined. The present study sought to determine whether myristate-derived d16 sphingolipids are represented among myocardial sphingolipids and, if so, whether their function and metabolic routes were distinct from those of palmitate-derived d18 sphingolipids. Data showed that d16:0 sphingoid bases occurred in more than one-third of total dihydrosphingosine and dihydroceramides in myocardium, and a diet high in saturated fat promoted their de novo production. Intriguingly, d16-ceramides demonstrated highly limited N-acyl chain diversity, and in vitro enzyme activity assays showed that these bases were utilized preferentially to canonical bases by CerS1. Functional differences between myristate- and palmitate-derived sphingolipids were observed in that, unlike d18 sphingolipids and SPTLC2, d16 sphingolipids and SPTLC3 did not appear to contribute to myristate-induced autophagy, whereas only d16 sphingolipids promoted cell death and cleavage of poly(ADP-ribose) polymerase in cardiomyocytes. Thus, these results reveal a previously unappreciated component of cardiac sphingolipids with functional differences from canonical sphingolipids.

Acid sphingomyelinase plays a key role in palmitic acid-amplified inflammatory signaling triggered by lipopolysaccharide at low concentrations in macrophages.

Periodontal disease is more prevalent and severe in patients with diabetes than in nondiabetic patients. In addition to diabetes, a large number of studies have demonstrated an association between obesity and chronic periodontal disease. However, the underlying mechanisms have not been well understood. Since plasma free fatty acids (FAs) are elevated in obese patients and saturated FAs such as palmitic acid (PA) have been shown to increase host inflammatory response, we sought to find out how PA interacts with lipopolysaccharide (LPS), an important pathological factor involved in periodontal disease, to enhance inflammation. We found that whereas low concentration of LPS (1 ng/ml) stimulated interleukin (IL)-6 expression in RAW 264.7 macrophages, PA further augmented it fourfold. Besides IL-6, PA amplified the stimulatory effect of LPS on a large amount of Toll-like receptor (TLR)4-mediated expression of proinflammatory signaling molecules such as IL-1 receptor-associated kinase-like 2 and proinflammatory molecules, including monocyte chemotactic protein-1 and colony-stimulating factor. We also observed that PA augmented TLR4 but not TLR2 signal, and the augmentation was mediated by nuclear factor-κB (NF-κB) pathways. To further elucidate the regulatory mechanism whereby PA amplifies LPS signal, our studies showed that PA and LPS synergistically increased hydrolysis of sphingomyelin by stimulating acid sphingomyelinase (ASMase) activity, which contributed to a marked increase in ceramide production and IL-6 upregulation. Taken together, this study has demonstrated that PA markedly augments TLR4-mediated proinflammatory signaling triggered by low concentration of LPS in macrophages, and ASMase plays a key role in the augmentation.

Prescribing Stimulants for Children and Adolescents With Attention-Deficit/Hyperactivity Disorder and Co-occurring Cannabis Use: Considerations for Managing a Clinical Dilemma.

Attention-deficit/hyperactivity disorder (ADHD) is highly prevalent in the pediatric population, with 11% of children and adolescents having ever been diagnosed with the disorder.1 The management of ADHD in the setting of co-occurring cannabis use, which is more prevalent in adolescents with ADHD than in the general population, is an increasingly common dilemma facing clinicians, in part due to recent changes in social acceptability, access, usage, and state-level legal status of cannabis.2 Clinicians face several considerations, including the following: the confounding effects of cannabis use on assessment and management of ADHD symptoms; the potential reduction in risk of substance use when ADHD symptoms are well managed; and the increased risk of misuse and diversion of stimulants in patients with ongoing cannabis use.2.

Treatment of Adults with Autism and Major Depressive Disorder Using Transcranial Magnetic Stimulation: An Open Label Pilot Study.

Patients with autism spectrum disorder (ASD) are at high risk for comorbid major depressive disorder (MDD), which can severely impair functioning and quality of life. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation technique, which is Food and Drug Administration (FDA) cleared for the treatment of MDD in adults. Despite demonstrated efficacy in the treatment of depression, there are limited data on the use of rTMS in patients with ASD and comorbid MDD. We hypothesized that a standard rTMS protocol for MDD would reduce depressive symptoms for adults with ASD and MDD. Secondarily, we investigated whether this treatment would also reduce core ASD symptoms. Participants of 18-65 years old with ASD and MDD without any medication changes in the last month were eligible for this open-label trial. Participants underwent 25 sessions of rTMS (figure-of-eight coil, 100-120% resting motor threshold, 10 Hz, 3,000 pulses per session) applied to the left dorsolateral prefrontal cortex. Thirteen participants enrolled in the study, with two withdrawing due to tolerability, and one excluded from analysis. Overall, side effects were mild and rTMS was well tolerated. The Hamilton rating scale for depression (HAM-D17 ) improved 13.5 points (IQR 5-15), and 40% of participants achieved remission (HAM-D17 ≤ 7) after rTMS treatment. Informant clinical scales of core symptoms of autism also suggested improvement with rTMS, though no change was observed by the participants themselves. Thus, this open-label trial suggests that high-frequency rTMS is well tolerated by adults with autism and MDD, with improvement in depressive symptoms and possible effects on core autism symptoms. Autism Res 2020, 13: 346-351. © 2020 International Society for Autism Research,Wiley Periodicals, Inc. LAY SUMMARY: This study evaluated the safety and effects of repetitive transcranial magnetic stimulation (rTMS) on depression and autism symptoms in individuals with both major depressive disorder and autism spectrum disorder. rTMS was well tolerated by the participants, depression improved with treatment, and family members' assessment of autism symptoms improved as well. This study supports the need for further work to evaluate rTMS in individuals who have both autism and depression.

Ceramide synthase 5 mediates lipid-induced autophagy and hypertrophy in cardiomyocytes.

Diabetic cardiomyopathy (DbCM), which consists of cardiac hypertrophy and failure in the absence of traditional risk factors, is a major contributor to increased heart failure risk in type 2 diabetes patients. In rodent models of DbCM, cardiac hypertrophy and dysfunction have been shown to depend upon saturated fatty acid (SFA) oversupply and de novo sphingolipid synthesis. However, it is not known whether these effects are mediated by bulk SFAs and sphingolipids or by individual lipid species. In this report, we demonstrate that a diet high in SFA induced cardiac hypertrophy, left ventricular systolic and diastolic dysfunction, and autophagy in mice. Furthermore, treatment with the SFA myristate, but not palmitate, induced hypertrophy and autophagy in adult primary cardiomyocytes. De novo sphingolipid synthesis was required for induction of all pathological features observed both in vitro and in vivo, and autophagy was required for induction of hypertrophy in vitro. Finally, we implicated a specific ceramide N-acyl chain length in this process and demonstrated a requirement for (dihydro)ceramide synthase 5 in cardiomyocyte autophagy and myristate-mediated hypertrophy. Thus, this report reveals a requirement for a specific sphingolipid metabolic route and dietary SFAs in the molecular pathogenesis of lipotoxic cardiomyopathy and hypertrophy.