The coordination of cellular biological processes is regulated in part via metabolic enzymes acting to match cellular metabolism to current conditions. The acetate activating enzyme, acyl-coenzyme A synthetase short-chain family member 2 (Acss2), has long been considered to have a predominantly lipogenic function. More recent evidence suggests that this enzyme has regulatory functions in addition to its role in providing acetyl-CoA for lipid synthesis. We used Acss2 knockout mice (Acss2^−/−) to further investigate the roles this enzyme plays in three physiologically distinct organ systems that make extensive use of lipid synthesis and storage, including the liver, brain, and adipose tissue. We examined the resulting transcriptomic changes resulting from Acss2 deletion and assessed these changes in relation to fatty acid constitution. We find that loss of Acss2 leads to dysregulation of numerous canonical signaling pathways, upstream transcriptional regulatory molecules, cellular processes, and biological functions, which were distinct in the liver, brain, and mesenteric adipose tissues. The detected organ-specific transcriptional regulatory patterns reflect the complementary functional roles of these organ systems within the context of systemic physiology. While alterations in transcriptional states were evident, the loss of Acss2 resulted in few changes in fatty acid constitution in all three organ systems. Overall, we demonstrate that Acss2 loss institutes organ-specific transcriptional regulatory patterns reflecting the complementary functional roles of these organ systems. Collectively, these findings provide further confirmation that Acss2 regulates key transcription factors and pathways under well-fed, non-stressed conditions and acts as a transcriptional regulatory enzyme.

There is a close relationship between cardiovascular disease and cardiac energy metabolism, and we have previously demonstrated that palmitate inhibits myocyte contraction by increasing Kv channel activity and decreasing the action potential duration. Glucose and long chain fatty acids are the major fuel sources supporting cardiac function; however, cardiac myocytes can utilize a variety of substrates for energy generation, and previous studies demonstrate the acetate is rapidly taken up and oxidized by the heart. In this study, we tested the effects of acetate on contractile function of isolated mouse ventricular myocytes. Acute exposure of myocytes to 10 mM sodium acetate caused a marked, but transient, decrease in systolic sarcomere shortening (1.49 ± 0.20% vs. 5.58 ± 0.49% in control), accompanied by a significant increase in diastolic sarcomere length (1.81 ± 0.01 μm vs. 1.77 ± 0.01 μm in control), with a near linear dose response in the 1–10 mM range. Unlike palmitate, acetate caused no change in action potential duration; however, acetate markedly increased mitochondrial Ca2+ uptake. Moreover, pretreatment of cells with the mitochondrial Ca2+ uptake blocker, Ru-360 (10 μM), markedly suppressed the effect of acetate on contraction. Lehninger and others have previously demonstrated that the anions of weak aliphatic acids such as acetate stimulate Ca2+ uptake in isolated mitochondria. Here we show that this effect of acetate appears to extend to isolated cardiac myocytes where it transiently modulates cell contraction.

Organophosphate (OP) insecticide poisoning remains a significant world health issue. Despite attempts to reduce OP insecticide use in some countries, they continue to be used extensively in many regions, putting agricultural workers at risk of excess exposure. Furthermore, the high toxicity and ready availability of OP insecticides in agricultural settings have created an additional public health issue due to their use in attempted suicides. Tens of thousands of people are admitted to hospitals every year after intentional ingestion of OP insecticides. The standard treatment regimen for OP poisoning can prevent mortality, even in some severe cases, but these treatments do not protect the central nervous system (CNS) from excitotoxic damage, and therefore, additional neuroprotective treatments are needed. One promising treatment is the use of halogenated ether anesthetics, including isoflurane, a common anesthetic available in hospitals throughout the world. Isoflurane can be administered by inhalation using vaporizer equipment, or it can be injected intravenously as a lipid–water emulsion. In both cases, excellent neuroprotection has been observed in preclinical models, even when administered up to 1 h after the onset of OP insecticide poisoning. Prolonged administration was not necessary for neuroprotective efficacy, with administration times of only 5 min being sufficient. Including inhalational anesthetics as an adjunct to the standard treatment for OP poisoning could significantly reduce chronic morbidities, especially long-term CNS damage. Research is ongoing to bring this promising treatment to human trials.

Coordination of cellular biological processes is regulated in part via metabolic enzymes acting to match cellular metabolism to current conditions. The acetate activating enzyme, acyl-coenzyme A synthetase short-chain family member 2 (Acss2) has long been considered to have a predominantly lipogenic function. More recent evidence suggests that this enzyme has regulatory functions in addition to its role in providing acetyl-CoA for lipid synthesis. We used Acss2 knockout mice (Acss2-/-) to further investigate the roles this enzyme plays in three physiologically distinct organ systems that make extensive use of lipid synthesis and storage including the liver, brain and adipose tissue. We examined the resulting transcriptomic changes resulting from Acss2 deletion and assessed these changes in relation to fatty acid constitution. We find that loss of Acss2 leads to dysregulation of numerous canonical signaling pathways, upstream transcriptional regulatory molecules, cellular processes, and biological functions, which were distinct in the liver, brain and mesenteric adipose tissues. The detected organ-specific transcriptional regulatory patterns reflect the complementary functional roles of these organ systems within the context of systemic physiology. While alterations in transcriptional states were evident, the loss of Acss2 resulted in few changes in fatty acid constitution in all three organ systems. Overall, we demonstrate Acss2 loss institutes organ-specific transcriptional regulatory patterns reflecting the complementary functional roles of these organ systems. Collectively, these findings provide further confirmation that Acss2 regulates key transcription factors and pathways under well-fed, non-stressed conditions, and acts as a transcriptional regulatory enzyme.

Organophosphate (OP) insecticide poisoning remains a significant world health issue. Despite attempts to reduce OP insecticide use in some countries, they continue to be used extensively in many regions, putting agriculture workers at risk of excess exposure. Further, the high toxicity and ready availability of OP insecticides in agricultural settings has created an additional public health issue due to their use in attempted suicides. Tens of thousands of people are admitted to hospitals every year after intentional ingestion of OP insecticides. The standard treatment regimen for OP poisoning can prevent mortality, even in some severe cases, but these treatments do not protect the central nervous system (CNS) from excitotoxic damage, and therefore additional neuroprotective treatments are needed. One promising treatment is the use of halogenated ether anesthetics including isoflurane, a common anesthetic available in hospitals throughout the world. Isoflurane can be administered by inhalation using vaporizer equipment, and can be injected intravenously as a lipid-water emulsion. In both cases, excellent neuroprotection has been observed in pre-clinical models, even when administered up to 1 hour after the onset of OP insecticide poisoning. Prolonged administration was not necessary for the neuroprotective efficacy, with administration times of only 5 minutes being sufficient. Research is ongoing to bring this promising treatment to human trials.