Polyunsaturated fatty acyl-coenzyme As are inhibitors of cholesterol biosynthesis in zebrafish and mice
SUMMARY Lipid disorders pose therapeutic challenges. Previously we discovered that mutation of the hepatocyte β-hydroxybutyrate transporter Slc16a6a in zebrafish causes hepatic steatosis during fasting, marked by increased hepatic triacylglycerol, but not cholesterol. This selective diversion of tra...
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The Company of Biologists
2013-11-01
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Series: | Disease Models & Mechanisms |
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doaj-369bad8cdc78497695ad9256e61354402020-11-25T01:23:34ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112013-11-01661365137710.1242/dmm.013425013425Polyunsaturated fatty acyl-coenzyme As are inhibitors of cholesterol biosynthesis in zebrafish and miceSanthosh KaranthVy My TranBalagurunathan KuberanAmnon SchlegelSUMMARY Lipid disorders pose therapeutic challenges. Previously we discovered that mutation of the hepatocyte β-hydroxybutyrate transporter Slc16a6a in zebrafish causes hepatic steatosis during fasting, marked by increased hepatic triacylglycerol, but not cholesterol. This selective diversion of trapped ketogenic carbon atoms is surprising because acetate and acetoacetate can exit mitochondria and can be incorporated into both fatty acids and cholesterol in normal hepatocytes. To elucidate the mechanism of this selective diversion of carbon atoms to fatty acids, we fed wild-type and slc16a6a mutant animals high-protein ketogenic diets. We find that slc16a6a mutants have decreased activity of the rate-limiting enzyme of cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcr), despite increased Hmgcr protein abundance and relative incorporation of mevalonate into cholesterol. These observations suggest the presence of an endogenous Hmgcr inhibitor. We took a candidate approach to identify such inhibitors. First, we found that mutant livers accumulate multiple polyunsaturated fatty acids (PUFAs) and PUFA-CoAs, and we showed that human HMGCR is inhibited by PUFA-CoAs in vitro. Second, we injected mice with an ethyl ester of the PUFA eicosapentaenoic acid and observed an acute decrease in hepatic Hmgcr activity, without alteration in Hmgcr protein abundance. These results elucidate a mechanism for PUFA-mediated cholesterol lowering through direct inhibition of Hmgcr.http://dmm.biologists.org/content/6/6/1365 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Santhosh Karanth Vy My Tran Balagurunathan Kuberan Amnon Schlegel |
spellingShingle |
Santhosh Karanth Vy My Tran Balagurunathan Kuberan Amnon Schlegel Polyunsaturated fatty acyl-coenzyme As are inhibitors of cholesterol biosynthesis in zebrafish and mice Disease Models & Mechanisms |
author_facet |
Santhosh Karanth Vy My Tran Balagurunathan Kuberan Amnon Schlegel |
author_sort |
Santhosh Karanth |
title |
Polyunsaturated fatty acyl-coenzyme As are inhibitors of cholesterol biosynthesis in zebrafish and mice |
title_short |
Polyunsaturated fatty acyl-coenzyme As are inhibitors of cholesterol biosynthesis in zebrafish and mice |
title_full |
Polyunsaturated fatty acyl-coenzyme As are inhibitors of cholesterol biosynthesis in zebrafish and mice |
title_fullStr |
Polyunsaturated fatty acyl-coenzyme As are inhibitors of cholesterol biosynthesis in zebrafish and mice |
title_full_unstemmed |
Polyunsaturated fatty acyl-coenzyme As are inhibitors of cholesterol biosynthesis in zebrafish and mice |
title_sort |
polyunsaturated fatty acyl-coenzyme as are inhibitors of cholesterol biosynthesis in zebrafish and mice |
publisher |
The Company of Biologists |
series |
Disease Models & Mechanisms |
issn |
1754-8403 1754-8411 |
publishDate |
2013-11-01 |
description |
SUMMARY
Lipid disorders pose therapeutic challenges. Previously we discovered that mutation of the hepatocyte β-hydroxybutyrate transporter Slc16a6a in zebrafish causes hepatic steatosis during fasting, marked by increased hepatic triacylglycerol, but not cholesterol. This selective diversion of trapped ketogenic carbon atoms is surprising because acetate and acetoacetate can exit mitochondria and can be incorporated into both fatty acids and cholesterol in normal hepatocytes. To elucidate the mechanism of this selective diversion of carbon atoms to fatty acids, we fed wild-type and slc16a6a mutant animals high-protein ketogenic diets. We find that slc16a6a mutants have decreased activity of the rate-limiting enzyme of cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcr), despite increased Hmgcr protein abundance and relative incorporation of mevalonate into cholesterol. These observations suggest the presence of an endogenous Hmgcr inhibitor. We took a candidate approach to identify such inhibitors. First, we found that mutant livers accumulate multiple polyunsaturated fatty acids (PUFAs) and PUFA-CoAs, and we showed that human HMGCR is inhibited by PUFA-CoAs in vitro. Second, we injected mice with an ethyl ester of the PUFA eicosapentaenoic acid and observed an acute decrease in hepatic Hmgcr activity, without alteration in Hmgcr protein abundance. These results elucidate a mechanism for PUFA-mediated cholesterol lowering through direct inhibition of Hmgcr. |
url |
http://dmm.biologists.org/content/6/6/1365 |
work_keys_str_mv |
AT santhoshkaranth polyunsaturatedfattyacylcoenzymeasareinhibitorsofcholesterolbiosynthesisinzebrafishandmice AT vymytran polyunsaturatedfattyacylcoenzymeasareinhibitorsofcholesterolbiosynthesisinzebrafishandmice AT balagurunathankuberan polyunsaturatedfattyacylcoenzymeasareinhibitorsofcholesterolbiosynthesisinzebrafishandmice AT amnonschlegel polyunsaturatedfattyacylcoenzymeasareinhibitorsofcholesterolbiosynthesisinzebrafishandmice |
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