Nicotinamide adenine dinucleotide biosynthesis and consumption in dysfunctional white adipocytes

In addition to its role in storage of dietary energy in a highly concentrated form, the white adipose tissue (WAT) is an active endocrine organ that regulates various physiological processes in the body. It plays a central role in insulin responsiveness and energy homeostasis, which is mediated by the action of a wide range of biologically active molecules - adipokines. During its “remodeling”, the obese WAT becomes inflamed and dysfunctional, which causes insulin resistance. Dysfunctional WAT in obesity exhibits increased production of reactive oxygen species (ROS) and decreased activity of some of the key antioxidant enzymes, which leads to oxidative stress. Indeed, protein carbonyls in the visceral adipose tissue are considered as a reliable biomarker of the level of oxidative stress in this tissue. Their negative correlation with serum adiponectin is indicative of systemic effects of oxidative stress in the visceral WAT. Glutathione S-transferase isoform A4 (GSTA4) has an important role in protection of the white adipocytes from oxidative stress and protein carbonylation. However, GstA4 is downregulated in adipocytes treated with tumor necrosis factor α (TNFα), as well as in adipose tissue from obese mice, suggesting the link between oxidative stress, inflammation and insulin resistance. GstA4 silenced 3T3L1s are a good experimental model to study the consequences of oxidative stress in dysfunctional adipocytes in obesity induced insulin resistance. Among other findings, it has been shown that the expression of Sirtuin 3 (Sirt3) is decreased in GstA4 silenced 3T3-L1 adipocytes (Bernlohr lab., unpublished results). Sirtuins are enzymes that deacetylate lysine residues on both histone and nonhistone proteins. Mammals have seven sirtuins with different subcellular localization. SIRT3 is located in mitochondria. There is evidence that SIRT3 can delay the onset of a number of oxidative stress- and age-related pathologies. Sirtuin activity is nicotinamide adenine dinucleotide (NAD+) dependent and is directly linked to the energetic and redox status of the cell. We explored the expression of some of the key genes involved in NAD+ biosynthesis and consumption in a model of inflamed white adipocytes. Our experiments demonstrated a significant disturbance of NAD+ metabolism, and decreased Sirt3 expression. These findings indicate that Sirt3 and NAD+ pathway can be considered as potential therapeutic targets in obesity induced insulin resistance

Revised nomenclature for the mammalian long-chain acyl-CoA synthetase gene family.

By consensus, the acyl-CoA synthetase (ACS) community, with the advice of the human and mouse genome nomenclature committees, has revised the nomenclature for the mammalian long-chain acyl-CoA synthetases. ACS is the family root name, and the human and mouse genes for the long-chain ACSs are termed ACSL1,3-6 and Acsl1,3-6, respectively. Splice variants of ACSL3, -4, -5, and -6 are cataloged. Suggestions for naming other family members and for the nonmammalian acyl-CoA synthetases are made

Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality

Programmed death ligand-1 (PD-L1) interaction with PD-1 induces T cell exhaustion and is a therapeutic target to enhance immune responses against cancer and chronic infections. In murine bone marrow transplant models, PD-L1 expression on host target tissues reduces the incidence of graft-versus-host disease (GVHD). PD-L1 is also expressed on T cells; however, it is unclear whether PD-L1 on this population influences immune function. Here, we examined the effects of PD-L1 modulation of T cell function in GVHD. In patients with severe GVHD, PD-L1 expression was increased on donor T cells. Compared with mice that received WT T cells, GVHD was reduced in animals that received T cells from Pdl1–/– donors. PD-L1–deficient T cells had reduced expression of gut homing receptors, diminished production of inflammatory cytokines, and enhanced rates of apoptosis. Moreover, multiple bioenergetic pathways, including aerobic glycolysis, oxidative phosphorylation, and fatty acid metabolism, were also reduced in T cells lacking PD-L1. Finally, the reduction of acute GVHD lethality in mice that received Pdl1–/– donor cells did not affect graft-versus-leukemia responses. These data demonstrate that PD-L1 selectively enhances T cell–mediated immune responses, suggesting a context-dependent function of the PD-1/PD-L1 axis, and suggest selective inhibition of PD-L1 on donor T cells as a potential strategy to prevent or ameliorate GVHD

Revised nomenclature for the mammalian long-chain acyl-CoA synthetase gene family: TABLE 1.

By consensus, the acyl-CoA synthetase (ACS) community, with the advice of the human and mouse genome nomenclature committees, has revised the nomenclature for the mammalian long-chain acyl-CoA synthetases. ACS is the family root name, and the human and mouse genes for the long-chain ACSs are terme

European contribution to the study of ROS: A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS).

The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the long run, to finding new therapeutic strategies to target dysregulated redox processes in various diseases. This report highlights the major achievements of EU-ROS as well as research updates and new perspectives arising from its members. The EU-ROS consortium comprised more than 140 active members who worked together for four years on the topics briefly described below. The formation of reactive oxygen and nitrogen species (RONS) is an established hallmark of our aerobic environment and metabolism but RONS also act as messengers via redox regulation of essential cellular processes. The fact that many diseases have been found to be associated with oxidative stress established the theory of oxidative stress as a trigger of diseases that can be corrected by antioxidant therapy. However, while experimental studies support this thesis, clinical studies still generate controversial results, due to complex pathophysiology of oxidative stress in humans. For future improvement of antioxidant therapy and better understanding of redox-associated disease progression detailed knowledge on the sources and targets of RONS formation and discrimination of their detrimental or beneficial roles is required. In order to advance this important area of biology and medicine, highly synergistic approaches combining a variety of diverse and contrasting disciplines are needed.The EU-ROS consortium (COST Action BM1203) was supported by the European Cooperation in Science and Technology (COST). The present overview represents the final Action dissemination summarizing the major achievements of COST Action BM1203 (EU-ROS) as well as research news and personal views of its members. Some authors were also supported by COST Actions BM1005 (ENOG) and BM1307 (PROTEOSTASIS), as well as funding from the European Commission FP7 and H2020 programmes, and several national funding agencies

Nicotinamide adenine dinucleotide biosynthesis and consumption in dysfunctional white adipocytes

In addition to its role in storage of dietary energy in a highly concentrated form, the white adipose tissue (WAT) is an active endocrine organ that regulates various physiological processes in the body. It plays a central role in insulin responsiveness and energy homeostasis, which is mediated by the action of a wide range of biologically active molecules - adipokines. During its “remodeling”, the obese WAT becomes inflamed and dysfunctional, which causes insulin resistance. Dysfunctional WAT in obesity exhibits increased production of reactive oxygen species (ROS) and decreased activity of some of the key antioxidant enzymes, which leads to oxidative stress. Indeed, protein carbonyls in the visceral adipose tissue are considered as a reliable biomarker of the level of oxidative stress in this tissue. Their negative correlation with serum adiponectin is indicative of systemic effects of oxidative stress in the visceral WAT. Glutathione S-transferase isoform A4 (GSTA4) has an important role in protection of the white adipocytes from oxidative stress and protein carbonylation. However, GstA4 is downregulated in adipocytes treated with tumor necrosis factor α (TNFα), as well as in adipose tissue from obese mice, suggesting the link between oxidative stress, inflammation and insulin resistance. GstA4 silenced 3T3L1s are a good experimental model to study the consequences of oxidative stress in dysfunctional adipocytes in obesity induced insulin resistance. Among other findings, it has been shown that the expression of Sirtuin 3 (Sirt3) is decreased in GstA4 silenced 3T3-L1 adipocytes (Bernlohr lab., unpublished results). Sirtuins are enzymes that deacetylate lysine residues on both histone and nonhistone proteins. Mammals have seven sirtuins with different subcellular localization. SIRT3 is located in mitochondria. There is evidence that SIRT3 can delay the onset of a number of oxidative stress- and age-related pathologies. Sirtuin activity is nicotinamide adenine dinucleotide (NAD+) dependent and is directly linked to the energetic and redox status of the cell. We explored the expression of some of the key genes involved in NAD+ biosynthesis and consumption in a model of inflamed white adipocytes. Our experiments demonstrated a significant disturbance of NAD+ metabolism, and decreased Sirt3 expression. These findings indicate that Sirt3 and NAD+ pathway can be considered as potential therapeutic targets in obesity induced insulin resistance