Inhibition of fatty acid metabolism ameliorates disease activity in an animal model of multiple sclerosis

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system and a leading cause of neurological disability. The complex immunopathology and variable disease course of multiple sclerosis have limited effective treatment of all patients. Altering the metabolism of immune cells may be an attractive strategy to modify their function during autoimmunity. We examined the effect of inhibiting fatty acid metabolism in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Mice treated with an inhibitor of carnitine palmitoyltransferase 1 (CPT-1), the rate-limiting enzyme in the beta-oxidation of fatty acids, showed a reduction in disease severity as well as less inflammation and demyelination. Inhibition of CPT-1 in encephalitogenic T-cells resulted in increased apoptosis and reduced inflammatory cytokine production. These results suggest that disruption of fatty acid metabolism promotes downregulation of inflammation in the CNS and that this metabolic pathway is a potential therapeutic target for multiple sclerosis

Life without Oxygen: Gene Regulatory Responses of the Crucian Carp (Carassius carassius) Heart Subjected to Chronic Anoxia

Crucian carp are unusual among vertebrates in surviving extended periods in the complete absence of molecular oxygen. During this time cardiac output is maintained though these mechanisms are not well understood. Using a high-density cDNA microarray, we have defined the genome-wide gene expression responses of cardiac tissue after exposing the fish at two temperatures (8 and 13°C) to one and seven days of anoxia, followed by seven days after restoration to normoxia. At 8°C, using a false discovery rate of 5%, neither anoxia nor re-oxygenation elicited appreciable changes in gene expression. By contrast, at 13°C, 777 unique genes responded strongly. Up-regulated genes included those involved in protein turnover, the pentose phosphate pathway and cell morphogenesis while down-regulated gene categories included RNA splicing and transcription. Most genes were affected between one and seven days of anoxia, indicating gene regulation over the medium term but with few early response genes. Re-oxygenation for 7 days was sufficient to completely reverse these responses. Glycolysis displayed more complex responses with anoxia up-regulated transcripts for the key regulatory enzymes, hexokinase and phosphofructokinase, but with down-regulation of most of the non-regulatory genes. This complex pattern of responses in genomic transcription patterns indicates divergent cardiac responses to anoxia, with the transcriptionally driven reprogramming of cardiac function seen at 13°C being largely completed at 8°C

Cellular metabolism at a glance

Metabolism is highly coordinated component of the cellular activity that involves sequential chemical transformations, within a so-called metabolic network. Through these coordinated actions, living organisms acquire energy and biosynthetic precursors to maintain cellular homeostasis and function. Metabolism relies on the breaking down of macromolecules to produce energy [catabolism] and/or intermediary metabolites that are then used to construct essential building blocks for macromolecule production [anabolism]. Overall, these metabolic processes are controlled by cellular energy status: when the energy released from catabolic processes exceeds the cellular demands the storage of metabolites in the form of lipids and glycogen takes place. These phenomena have been vastly associated with the genesis of metabolic disorders, such as obesity. In recent years, we have assisted to a rediscovery of metabolism through the identification of metabolic intermediaries that act as key players on differentiation, proliferation, and function of immune cells. This recent acknowledgement of the impact of metabolism in the overall immune response originated the ground-breaking field of immunometabolism. Here, we will provide a holistic view of metabolism highlighting the biochemical principles underlying its regulation.(undefined)info:eu-repo/semantics/publishedVersio