Peroxisomal acyl-CoA synthetases

AbstractPeroxisomes carry out many essential lipid metabolic functions. Nearly all of these functions require that an acyl group—either a fatty acid or the acyl side chain of a steroid derivative—be thioesterified to coenzyme A (CoA) for subsequent reactions to proceed. This thioesterification, or “activation”, reaction, catalyzed by enzymes belonging to the acyl-CoA synthetase family, is thus central to cellular lipid metabolism. However, despite our rather thorough understanding of peroxisomal metabolic pathways, surprisingly little is known about the specific peroxisomal acyl-CoA synthetases that participate in these pathways. Of the 26 acyl-CoA synthetases encoded by the human and mouse genomes, only a few have been reported to be peroxisomal, including ACSL4, SLC27A2, and SLC27A4. In this review, we briefly describe the primary peroxisomal lipid metabolic pathways in which fatty acyl-CoAs participate. Then, we examine the evidence for presence and functions of acyl-CoA synthetases in peroxisomes, much of which was obtained before the existence of multiple acyl-CoA synthetase isoenzymes was known. Finally, we discuss the role(s) of peroxisome-specific acyl-CoA synthetase isoforms in lipid metabolism. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of Peroxisomes in Health and Disease

Extended Cave Drip Water Time Series Captures the 2015–2016 El Niño in Northern Borneo

Time series of cave drip water oxygen isotopes (δ18O) provide site‐specific assessments of the contributions of climate and karst processes to stalagmite δ18O records employed for hydroclimate reconstructions. We present ~12‐year‐long time series of biweekly cave drip water δ18O variations from three sites as well as a daily resolved local rainfall δ18O record from Gunung Mulu National Park in northern Borneo. Drip water δ18O variations closely match rainfall δ18O variations averaged over the preceding 3–18 months. We observe coherent interannual drip water δ18O variability of ~3‰ to 5‰ related to the El Niño–Southern Oscillation (ENSO), with sustained positive rainfall and drip water δ18O anomalies observed during the 2015/2016 El Niño. Evidence of nonlinear behavior at one of three drip water monitoring sites implies a time‐varying contribution from a longer‐term reservoir. Our results suggest that well‐replicated, high‐resolution stalagmite δ18O reconstructions from Mulu could characterize past ENSO‐related variability in regional hydroclimate.Plain Language SummaryCave stalagmites allow for the reconstruction of past regional rainfall variability over the last hundreds of thousands of years with robust age control. Such reconstructions rely on the fact that differences in the isotopic composition of rainwater set by regional rainfall patterns is preserved as the rainwater travels through cave bedrock to feed the cave drip waters forming stalagmites. Long‐term monitoring of rainwater and cave drip water isotopes ground truth the climate to stalagmite relationship across modern‐day changes in regional rainfall. Twelve years of monitoring data presented in this study identify individual El Niño–Southern Oscillation events in rainfall and cave drip water isotopic composition, providing a strong foundation for stalagmite‐based climate reconstructions from this site.Key PointsThree 12‐year‐long cave drip water δ18O time series capture El Niño and La Niña events in northern BorneoEstimates of karst residence times range from 3 to 18 months, with a secondary contribution from a longer‐term reservoir at one drip siteDrip water nonstationarity implies multiple stalagmites are required to reconstruct El Niño–Southern Oscillation variability over timePeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154266/1/grl60264-sup-0002-2019GL086363-SI.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154266/2/grl60264_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154266/3/grl60264.pd

Acyl-coenzyme A synthetases in metabolic control

The 11 long-chain (ACSL) and very long chain acyl-coenzyme A (acyl-CoA) synthetases [(ACSVL)/fatty acid transport protein] are receiving considerable attention because it has become apparent that their individual functions are not redundant

Mouse Betaine-Homocysteine S -Methyltransferase Deficiency Reduces Body Fat via Increasing Energy Expenditure and Impairing Lipid Synthesis and Enhancing Glucose Oxidation in White Adipose Tissue

Betaine-homocysteine S-methyltransferase (BHMT) catalyzes the synthesis of methionine from homocysteine. In our initial report, we observed a reduced body weight in Bhmt−/− mice. We initiated this study to investigate the potential role of BHMT in energy metabolism. Compared with the controls (Bhmt+/+), Bhmt−/− mice had less fat mass, smaller adipocytes, and better glucose and insulin sensitivities. Compared with the controls, Bhmt−/− mice had increased energy expenditure, with no changes in food intake, fat uptake or absorption, or in locomotor activity. The reduced adiposity in Bhmt−/− mice was not due to hyperthermogenesis. Bhmt−/− mice failed to maintain a normal body temperature upon cold exposure because of limited fuel supplies. In vivo and ex vivo tests showed that Bhmt−/− mice had normal lipolytic function. The rate of 14C-labeled fatty acid incorporated into [14C]triacylglycerol was the same in Bhmt+/+ and Bhmt−/− gonadal fat depots (GWAT), but it was 62% lower in Bhmt−/− inguinal fat depots (IWAT) compared with that of Bhmt+/+ mice. The rate of 14C-labeled fatty acid oxidation was the same in both GWAT and IWAT from Bhmt+/+ and Bhmt−/− mice. At basal level, Bhmt−/− GWAT had the same [14C]glucose oxidation as did the controls. When stimulated with insulin, Bhmt−/− GWAT oxidized 2.4-fold more glucose than did the controls. Compared with the controls, the rate of [14C]glucose oxidation was 2.4- and 1.8-fold higher, respectively, in Bhmt−/− IWAT without or with insulin stimulus. Our results show for the first time a role for BHMT in energy homeostasis

GNOSIS: the first instrument to use fibre Bragg gratings for OH suppression

GNOSIS is a prototype astrophotonic instrument that utilizes OH suppression fibres consisting of fibre Bragg gratings and photonic lanterns to suppress the 103 brightest atmospheric emission doublets between 1.47-1.7 microns. GNOSIS was commissioned at the 3.9-meter Anglo-Australian Telescope with the IRIS2 spectrograph to demonstrate the potential of OH suppression fibres, but may be potentially used with any telescope and spectrograph combination. Unlike previous atmospheric suppression techniques GNOSIS suppresses the lines before dispersion and in a manner that depends purely on wavelength. We present the instrument design and report the results of laboratory and on-sky tests from commissioning. While these tests demonstrated high throughput and excellent suppression of the skylines by the OH suppression fibres, surprisingly GNOSIS produced no significant reduction in the interline background and the sensitivity of GNOSIS and IRIS2 is about the same as IRIS2. It is unclear whether the lack of reduction in the interline background is due to physical sources or systematic errors as the observations are detector noise-dominated. OH suppression fibres could potentially impact ground-based astronomy at the level of adaptive optics or greater. However, until a clear reduction in the interline background and the corresponding increasing in sensitivity is demonstrated optimized OH suppression fibres paired with a fibre-fed spectrograph will at least provide a real benefits at low resolving powers.Comment: 15 pages, 13 figures, accepted to A

Deficiency of cardiac Acyl-CoA synthetase-1 induces diastolic dysfunction, but pathologic hypertrophy is reversed by rapamycin

In mice with temporally-induced cardiac-specific deficiency of acyl-CoA synthetase-1 (Acsl1H−/−), the heart is unable to oxidize long-chain fatty acids and relies primarily on glucose for energy. These metabolic changes result in the development of both a spontaneous cardiac hypertrophy and increased phosphorylated S6 kinase (S6K), a substrate of the mechanistic target of rapamycin, mTOR. Doppler echocardiography revealed evidence of significant diastolic dysfunction, indicated by a reduced E/A ratio and increased mean performance index, although the deceleration time and the expression of sarco/endoplasmic reticulum calcium ATPase and phospholambin showed no difference between genotypes. To determine the role of mTOR in the development of cardiac hypertrophy, we treated Acsl1H−/− mice with rapamycin. Six to eight week old Acsl1H−/− mice and their littermate controls were given i.p. tamoxifen to eliminate cardiac Acsl1, then concomitantly treated for 10 weeks with i.p. rapamycin or vehicle alone. Rapamycin completely blocked the enhanced ventricular S6K phosphorylation and cardiac hypertrophy and attenuated the expression of hypertrophy-associated fetal genes, including α-skeletal actin and B-type natriuretic peptide. mTOR activation of the related Acsl3 gene, usually associated with pathologic hypertrophy, was also attenuated in the Acsl1H−/− hearts, indicating that alternative pathways of fatty acid activation did not compensate for the loss of Acsl1. Compared to controls, Acsl1H−/− hearts exhibited an 8-fold higher uptake of 2-deoxy[1-14C]glucose and a 35% lower uptake of the fatty acid analog 2-bromo[1-14C]palmitate. These data indicate that Acsl1-deficiency causes diastolic dysfunction and that mTOR activation is linked to the development of cardiac hypertrophy in Acsl1H−/− mice

Mice Deficient in Glycerol-3-Phosphate Acyltransferase-1 Have a Reduced Susceptibility to Liver Cancer

The risk of hepatocellular carcinoma increases with the persistence of non-alcoholic fatty liver disease. Triacylglycerol synthesis is initiated by glycerol-3-phosphate acyltransferase (GPAT). Of four isoforms, GPAT1 contributes 30–50% of total liver GPAT activity, and we hypothesized that it might influence liver susceptibility to tumorigenesis. C57Bl/6 mice deficient in GPAT1 were backcrossed 6 times to C3H mice. After exposure to the carcinogen diethylnitrosamine (DEN) and the tumor promoter phenobarbital, male Gpat1−/− mice, compared with controls (Gpat1+/+), had 93% fewer macroscopically visible nodules per liver at 21 weeks of age and 39% fewer at 34 weeks of age. Microscopically, control mice had increased numbers of foci of altered hepatocytes, particularly the basophilic subtype, as well as more, and malignant, liver neoplasms than did the Gpat1−/− mice. At 21 weeks of age, 50% (4/8) of control mice (50%) had hepatocellular adenomas with an average multiplicity (tumors per tumor-bearing-animal) of 4.3, while none occurred in 8 Gpat1−/− mice. At 34 weeks of age, all 15 control mice (100%) had hepatocellular adenomas with an average multiplicity of 5.2 compared to an incidence of 93% in Gpat1−/− mice and multiplicity of 3.1. HCCs were observed in 13% of control mice and in only 6% of Gpat1−/− mice. These data show that alterations in the formation of complex lipids catalyzed by Gpat1 reduce susceptibility to DEN-induced liver tumorigenesis

Epigenetic regulation of COL15A1 in smooth muscle cell replicative aging and atherosclerosis

Smooth muscle cell (SMC) proliferation is a hallmark of vascular injury and disease. Global hypomethylation occurs during SMC proliferation in culture and in vivo during neointimal formation. Regardless of the programmed or stochastic nature of hypomethylation, identifying these changes is important in understanding vascular disease, as maintenance of a cells' epigenetic profile is essential for maintaining cellular phenotype. Global hypomethylation of proliferating aortic SMCs and concomitant decrease of DNMT1 expression were identified in culture during passage. An epigenome screen identified regions of the genome that were hypomethylated during proliferation and a region containing Collagen, type XV, alpha 1 (COL15A1) was selected by ‘genomic convergence' for characterization. COL15A1 transcript and protein levels increased with passage-dependent decreases in DNA methylation and the transcript was sensitive to treatment with 5-Aza-2′-deoxycytidine, suggesting DNA methylation-mediated gene expression. Phenotypically, knockdown of COL15A1 increased SMC migration and decreased proliferation and Col15a1 expression was induced in an atherosclerotic lesion and localized to the atherosclerotic cap. A sequence variant in COL15A1 that is significantly associated with atherosclerosis (rs4142986, P = 0.017, OR = 1.434) was methylated and methylation of the risk allele correlated with decreased gene expression and increased atherosclerosis in human aorta. In summary, hypomethylation of COL15A1 occurs during SMC proliferation and the consequent increased gene expression may impact SMC phenotype and atherosclerosis formation. Hypomethylated genes, such as COL15A1, provide evidence for concomitant epigenetic regulation and genetic susceptibility, and define a class of causal targets that sit at the intersection of genetic and epigenetic predisposition in the etiology of complex diseas