Nonoxidative ethanol metabolism: formation of fatty acid ethyl esters by cholesterol esterase.

Lange, Louis G.

doi:10.1073/pnas.79.13.3954

Cited by 89 publications

(48 citation statements)

References 30 publications

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“…11,12 Pancreatic homogenates were also noted to have an ability to synthesize FAEEs from FAs and ethanol,20,23 and the putative enzyme for this was thought to be a lipase. 24,25 It has been shown that the FAEE synthase activity of the putative enzyme exceeds its lipolytic capacity by several fold. 25 Triglyceride (TG) forms >80% of the adipocyte mass, 26e28 oleic acid (OA) being the most enriched FA.…”

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confidence: 99%

Fatty Acid Ethyl Esters Are Less Toxic Than Their Parent Fatty Acids Generated during Acute Pancreatitis

Patel

Durgampudi

Noel

et al. 2016

The American Journal of Pathology

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Although ethanol causes acute pancreatitis (AP) and lipolytic fatty acid (FA) generation worsens AP, the contribution of ethanol metabolites of FAs, ie, FA ethyl esters (FAEEs), to AP outcomes is unclear. Previously, pancreata of dying alcoholics and pancreatic necrosis in severe AP, respectively, showed high FAEEs and FAs, with oleic acid (OA) and its ethyl esters being the most abundant. We thus compared the toxicities of FAEEs and their parent FAs in severe AP. Pancreatic acini and peripheral blood mononuclear cells were exposed to FAs or FAEEs in vitro. The triglyceride of OA (i.e., glyceryl tri-oleate) or OAEE was injected into the pancreatic ducts of rats, and local and systemic severities were studied. Unsaturated FAs at equimolar concentrations to FAEEs induced a larger increase in cytosolic calcium, mitochondrial depolarization, and necro-apoptotic cell death. Glyceryl tri-oleate but not OAEE resulted in 70% mortality with increased serum OA, a severe inflammatory response, worse pancreatic necrosis, and multisystem organ failure. Our data show that FAs are more likely to worsen AP than FAEEs. Our observations correlate well with the high pancreatic FAEE concentrations in alcoholics without pancreatitis and high FA concentrations in pancreatic necrosis. Thus, conversion of FAs to FAEE may ameliorate AP in alcoholics. (Am J Pathol 2016, 186: 874e884; http://dx.doi.org/10.1016/j.ajpath.2015 Although fat necrosis has been associated with severe cases of pancreatitis for more than a century, 1,2 and alcohol consumption is a well-known risk factor for acute pancreatitis (AP), 3 only recently have we started understanding the mechanistic basis of these observations. 4e7 High amounts of unsaturated fatty acids (UFAs) have been noted in the pancreatic necrosis and sera of severe AP (SAP) patients by multiple groups. 8e12 These high UFAs seem pathogenically relevant because several studies show UFAs can cause pancreatic acinar injury or can worsen AP. 11e14 Ethanol may play a role in AP by distinct mechanisms, 3 including a worse inflammatory response to cholecystokinin, 4 increased zymogen activation, 15 basolateral enzyme release, 16 sensitization to stress, 7 FA ethyl esters (FAEEs), 17 cytosolic calcium, 18 and cell death. 19 Because the nonoxidative ethanol metabolite of fatty acids (FAs), FAEEs, were first noted to be elevated in the pancreata of dying alcoholics, they have been thought to play a role in AP. 17,19À22 Conclusive proof of the role of FAEEs in AP in comparison with their parent UFAs is lacking. Uncontrolled release of lipases into fat, whether in the pancreas or in the peritoneal cavity, may result in fat necrosis, UFA generation, which has been associated with SAP. 11,12 Pancreatic homogenates were also noted to have an ability to synthesize FAEEs from FAs and ethanol,20,23 and the putative enzyme for this was thought to be a lipase. 24,25 It has been shown that the FAEE synthase activity of the putative enzyme exceeds its lipolytic capacity by several fold. 25 Triglyceride (TG) forms >80% ...

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confidence: 99%

Fatty Acid Ethyl Esters Are Less Toxic Than Their Parent Fatty Acids Generated during Acute Pancreatitis

Patel

Durgampudi

Noel

et al. 2016

The American Journal of Pathology

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“…FAEE of predominantly ethyl palmitate (2.7-3.7 nmol/g tissue), ethyl stearate (4.0-5.5 nmol/g tissue), and ethyl oleate (2.1-2.7 nmol/g tissue) could be detected. 7 placenta. The presence of FAEE synthase in placenta on gestational d 7 with resultant FAEE accumulation and persistence of FAEE for at least 7 d was suggested by the following experiment.…”

Section: Retention Timementioning

confidence: 99%

“…Nonoxidative metabolism of ethanol to FAEE occurs in both liver and extrahepatic tissues (7) and is catalyzed by FAEE synthases. These lipids have been shown to bind to mitochondria in intact cells and to uncouple oxidative phosphorylation in mitochondrial preparations in vivo (8).…”

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confidence: 99%

Fetal Alcohol Syndrome and Fatty Acid Ethyl Esters

et al. 1992

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ABSTRACT. Fetal alcohol syndrome is the leading known cause of mental retardation. The syndrome, defined as growth retardation, midface hypoplasia, and neurologic dysfunction, represents only part of the spectrum of fetal alcohol effects. The biochemical mechanism of teratogenesis is unknown. In adults, metabolites of ethanol, FAEE, are known to accumulate in major organs. The formation of FAEE is catalyzed by a family of enzymes, FAEE synthases. Our hypothesis is that accumulation of FAEE in the embryo results in fetal alcohol syndrome. We have developed assays for FAEE and FAEE synthase activity using mg of tissue. Using these assays, we have shown the following: Human placenta, mouse placenta, heart, and liver are active in catalyzing the formation of FAEE. One h after maternal ethanol administration on gestational d 14, mouse placenta and fetuses accumulated significant quantities of FAEE. The fatty acid incorporated into FAEE was tissue dependent. Tissues from pregnant animals given ethanol on gestational d 7 showed persistence of FAEE on gestational d 14. We conclude that: 1 ) human and mouse placentas have significant FAEE synthase activity, 2) mouse heart, liver, placenta, and fetal tissues accumulate significant amounts of FAEE after maternal ethanol exposure, 3) there is tissue specificity for the fatty acid incorporated into FAEE, and 4) FAEE may persist for 7 d in placentas. These results provide a basis for further research into the role of FAEE in the development of fetal alcohol syndrome. (Pediatr Res 31: 492-495, 1992)

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“…Porcine pCEase was purchased from Worthington Biochemical Corp. (Freehold, NJ, USA) and dissolved in the same Tris buffer. CEase activities in various sources were determined by hydrolysis of cholesteryl-14C-oleate to cholesterol and 14C -oleic acid (10)(11)(12) . The reaction mixture (total volume of 0.2 ml) consisting of L-a-lysophosphatidylcholine, cholesteryl-14C-oleate, enzyme protein, DMSO containing the dissolved test compound, 0.1 M Tris-HC1 buffer (pH 7.5, nCEase; pH 7.0, pCEase) or 0.1 M acetic buffer (pH 4.5, aCEase) and saline was incubated for 1 hr at 371C (duplicate or triplicate assays).…”

Section: Hmg-coa Reductase Assaymentioning

confidence: 99%

Studies on Acyl-CoA:Cholesterol Acyltransferase (ACAT) Inhibitory Effects and Enzyme Selectivity of F-1394, a Pantotheic Acid Derivative

Kusunoki

Aragane

Yamaura

et al. 1995

Japanese Journal of Pharmacology

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ABSTRACT-(ls,2s)-2-[3-(2,2-Dimethylpropyl)-3-nonylureido]aminocyclohexane-l-yl 3-[N-(2,2, 5, 5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionate (F-1394), a pantotheic acid derivative, is a newly synthesized inhibitor of acyl-CoA: cholesterol acyltransferase (ACAT). In the present study, we investigated the inhibitory effects of F-1394 on the activities of ACAT. F-1394 reduced the ACAT activities in rat liver microsomes, homogenate of rabbit small intestinal mucosa and lysate of J774 macrophages with IC50 values of 6.4 nM, 10.7 nM and 32 nM, respectively. The kinetic studies showed that F-1394 exerted competitivetype inhibition, and the K; values in liver and small intestinal ACAT were 4.0 nM and 9.9 nM, respectively. The inhibitory effects of F-1394 on the activity of ACAT were more potent than that of other ACAT inhibitors or hypolipidemic agents. The study on enzyme selectivity indicated that F-1394 did not affect 3-hydroxy-3-methylglutaryl CoA reductase, acyl-CoA synthetase and cholesterol esterase. F-1394 weakly inhibited the activity of lecithine:cholesterol acyltransferase (LCAT) originating from rat plasma. The inhibitory potency of F-1394 for the activity of liver microsomal ACAT was 4,690-fold stronger than that for the activity of LCAT. These findings indicate that F-1394 is a potent and selective inhibitor of ACAT, and its inhibition manner is the competitive tune.

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Nonoxidative ethanol metabolism: formation of fatty acid ethyl esters by cholesterol esterase.

Cited by 89 publications

References 30 publications

Fatty Acid Ethyl Esters Are Less Toxic Than Their Parent Fatty Acids Generated during Acute Pancreatitis

Fatty Acid Ethyl Esters Are Less Toxic Than Their Parent Fatty Acids Generated during Acute Pancreatitis

Fetal Alcohol Syndrome and Fatty Acid Ethyl Esters

Studies on Acyl-CoA:Cholesterol Acyltransferase (ACAT) Inhibitory Effects and Enzyme Selectivity of F-1394, a Pantotheic Acid Derivative

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