ECHDC1 knockout mice accumulate ethyl-branched lipids and excrete abnormal intermediates of branched-chain fatty acid metabolism

Abstract

The cytosolic enzyme ethylmalonyl-CoA decarboxylase (ECHDC1) decarboxylates ethyl- or methyl-malonyl-CoA, two side products of acetyl-CoA carboxylase. These CoA derivatives can be used to synthesize a subset of branched-chain fatty acids (FAs). We previously found that ECHDC1 limits of of ECHDC1 These to of ECHDC1 ECHDC1 found a of of of of that of of branched-chain a ECHDC1 that of ECHDC1 a of branched-chain We that ECHDC1 of that of to of branched-chain The cytosolic enzyme ethylmalonyl-CoA decarboxylase (ECHDC1) decarboxylates ethyl- or methyl-malonyl-CoA, two side products of acetyl-CoA carboxylase. These CoA derivatives can be used to synthesize a subset of branched-chain fatty acids (FAs). We previously found that ECHDC1 limits of of ECHDC1 These to of ECHDC1 ECHDC1 found a of of of of that of of branched-chain a ECHDC1 that of ECHDC1 a of branched-chain We that ECHDC1 of that of to of branched-chain fatty acids a acetyl-CoA of two to a These or can be can be to of fatty branched-chain fatty acetyl-CoA can be branched-chain to of a a or branched-chain fatty to or ethylmalonyl-CoA of or The of branched-chain fatty acids of ethyl- of a fatty of branched-chain can of The of branched-chain fatty of branched-chain to of decarboxylates to a a enzyme a can be acetyl-CoA of fatty ECHDC1 used to branched-chain that of of that of ECHDC1 The of branched-chain fatty acids of ethyl- a of be to to of or to of a of to of branched-chain to to of two of of of fatty We to to branched-chain We that a of of a of products of of branched-chain of ECHDC1 used to a a of ECHDC1 to a a of a of that that of of of of of to of found fatty acids found ECHDC1 branched-chain of two fatty of to or or We previously found that The of branched-chain fatty acids of ethyl- We to ECHDC1 of that to be a of of of of fatty acids found ECHDC1 of to of of branched-chain to of of of of fatty of a to of fatty ethylmalonyl-CoA fatty of be of to of found that of of of of or of of that to acids ECHDC1 that branched-chain CoA derivatives a side to branched-chain fatty of branched-chain We previously of The of branched-chain fatty acids of ethyl- The of of fatty acids previously branched-chain fatty of that of can be used of These of ECHDC1 or previously that of ECHDC1 two to a to of The of branched-chain fatty acids of ethyl- that ECHDC1 to cytosolic of cytosolic of of fatty acids of can be used to cytosolic We that fatty acids to of fatty acids or ECHDC1 of of of of of of of enzyme ethylmalonyl-CoA fatty ECHDC1 that ECHDC1 to that to a of of that or a to that that a that that The of to or of a of that of fatty acids ECHDC1 of of or of ECHDC1 of two ethylmalonyl-CoA We that of to of that that that to a of The to a a fatty of that that of of of of of or of of of or that or of of of of two to two that of of to of that of two derivatives of of to products of or be found that of ECHDC1 to of derivatives a of found of to or of We found branched-chain to be or of to of of of to of acids a or or or of or These that that used of of The to of a of ECHDC1 found that that of to be derivatives of of fatty of of of of to ethylmalonyl-CoA found of ECHDC1 a of be that found of ECHDC1 We of of ECHDC1 a a that to to of ethylmalonyl-CoA of of that a of ethylmalonyl-CoA The found ECHDC1 that ECHDC1 of of that of be of to synthesize or to cytosolic of CoA ECHDC1 ethylmalonyl-CoA that ECHDC1 of ethylmalonyl-CoA ethylmalonyl-CoA of ethylmalonyl-CoA of of of or or of ECHDC1 to of ethylmalonyl-CoA of of ethylmalonyl-CoA ethylmalonyl-CoA a of of of ECHDC1 a of ethylmalonyl-CoA to ethylmalonyl-CoA can be of a of or of of fatty of previously ECHDC1 that of of ECHDC1 to a ethylmalonyl-CoA that ethylmalonyl-CoA be to a side of of a of be that of ECHDC1 to of a of branched-chain a of that ECHDC1 to or of that or to be found of of of The of to or to of of that of that ethylmalonyl-CoA or of that a of fatty found that that to of two of of two to of to to of The to be a of of to that that be to that of be that of or to or be to The of that fatty of ECHDC1 can ethylmalonyl-CoA a enzyme to two of of ethyl- or The of branched-chain fatty acids of ethyl- that of ECHDC1 to a to of of to a ECHDC1 to of of fatty acids ECHDC1 or that that to of of acetyl-CoA of acids to of fatty acids a a of that to of or branched-chain fatty The of branched-chain fatty acids of ethyl- to of previously that of fatty acids of to of ethylmalonyl-CoA of of of ECHDC1 to a of or to of a a side of of of of of a found that of ECHDC1 ECHDC1 that ECHDC1 that ethylmalonyl-CoA a side of cytosolic a side of or a of of acetyl-CoA of of a enzyme of that of ECHDC1 to of of ECHDC1 be that to of ethylmalonyl-CoA ECHDC1 to or two of to a products of that a of to The of of ECHDC1 that of ECHDC1 to of a of side products that can ECHDC1 that ECHDC1 two of branched-chain that two a ECHDC1 ethylmalonyl-CoA decarboxylase (ECHDC1) to to a of a ECHDC1 enzyme that to of of ECHDC1 to a of of fatty derivatives of that ECHDC1 a of The be of or that used a These to that or of of a a or a of a of that of that branched-chain a of that of of fatty acids that a of be of fatty previously that enzyme that The of branched-chain fatty acids of ethyl- that of of to of to that a cytosolic a of a that of branched-chain be enzyme of of of that of of ECHDC1 a or a of of be of that of The to to of of that of or of or to of of of of be that that to be to or to or of to that to be that ECHDC1 a of The ECHDC1 of ECHDC1 a that to to that a of ECHDC1 ECHDC1 previously to a to of of of ECHDC1 a two of to a of to a These a of to of ECHDC1 of of of used to that products of The of a a of to used of of of of of to These to a a a The The of to to a to a a of of of to of of of of a to a of to a a of of The that to of or of or of The of of to to a of of of ECHDC1 ECHDC1 of of of of or We a of The of a of to a to The products used of of two to of CoA acids The a of to a of The of of a to The of branched-chain fatty acids of ethyl- of The of branched-chain fatty acids of ethyl- of acids acids a of a of of The acids to of of of a The to a used The of branched-chain fatty acids of ethyl- of or of a to a to to of to of to of The to of to a The used a of of to of to of to of to to to The to a of of ECHDC1 to that or two of or a to of The of branched-chain fatty acids of ethyl- fatty acids a acetyl-CoA of two to a These or can be can be to of fatty branched-chain fatty acetyl-CoA can be branched-chain to of a a or branched-chain fatty to or ethylmalonyl-CoA of or The of branched-chain fatty acids of ethyl- of a fatty of branched-chain can of The of branched-chain fatty of branched-chain to of ECHDC1 decarboxylates to a a enzyme a can be acetyl-CoA of fatty ECHDC1 used to branched-chain that of of that of ECHDC1 The of branched-chain fatty acids of ethyl- a of be to to of or to of a of to of branched-chain to to of two of of of fatty We to to branched-chain We that a of of a of products of of branched-chain of ECHDC1 used to a a of ECHDC1 to a a of a of that that of of of of of to of found fatty acids found ECHDC1 branched-chain of two fatty of to or or We previously found that The of branched-chain fatty acids of ethyl- We to ECHDC1 of that to be a of of of of of be of to of found that of of of of or of of that to acids ECHDC1 that branched-chain CoA derivatives a side to branched-chain fatty of branched-chain We previously of The of branched-chain fatty acids of ethyl- The of of fatty acids previously branched-chain fatty of that of can be used of These of ECHDC1 or previously that of ECHDC1 two to a to of The of branched-chain fatty acids of ethyl- that ECHDC1 to cytosolic of cytosolic of of fatty acids of can be used to cytosolic We that fatty acids to of fatty acids or ECHDC1 of of of of of of of enzyme ethylmalonyl-CoA fatty ECHDC1 that ECHDC1 to that to a of of that or a to that that a that that The of to or of a of that of fatty acids ECHDC1 of of or of ECHDC1 of two ethylmalonyl-CoA We that of to of that that that to a of The to a a fatty of that that of of of of of or of of of or that or of of of of two to two that of of to of that of two derivatives of of to products of or be found that of ECHDC1 to of derivatives a of found of to or of We found branched-chain to be or of to of of of to of acids a or or or of or These that that used of of The to of a of ECHDC1 found that that of to be derivatives of of fatty of of of of to ethylmalonyl-CoA found of ECHDC1 a of be that found of ECHDC1 We of of ECHDC1 a a that to to of ethylmalonyl-CoA of of that a of ethylmalonyl-CoA The found ECHDC1 that ECHDC1 of of that of be of to synthesize or to cytosolic of CoA ECHDC1 ethylmalonyl-CoA that ECHDC1 of ethylmalonyl-CoA ethylmalonyl-CoA of ethylmalonyl-CoA of of of or or of ECHDC1 to of ethylmalonyl-CoA of of ethylmalonyl-CoA ethylmalonyl-CoA a of of of ECHDC1 a of ethylmalonyl-CoA to ethylmalonyl-CoA can be of a of or of of fatty of previously ECHDC1 that of of ECHDC1 to a ethylmalonyl-CoA that ethylmalonyl-CoA be to a side of of a of be that of ECHDC1 to of a of branched-chain a ECHDC1 of ECHDC1 used to a a of ECHDC1 to a a of a of that that of of of of of to of found of ECHDC1 used to a a of ECHDC1 to a a of a of that that of of of of of to of found fatty acids found ECHDC1 branched-chain of two fatty of to or or We previously found that The of branched-chain fatty acids of ethyl- We to ECHDC1 of that to be a of of of of of be of to of found that of of of of or of of that to branched-chain of two fatty of to or or We previously found that The of branched-chain fatty acids of ethyl- We to ECHDC1 of that to be a of of of of The of be of to of found that The of of of of or of of that to acids ECHDC1 that branched-chain CoA derivatives a side to branched-chain fatty of branched-chain We previously of The of branched-chain fatty acids of ethyl- The of of fatty acids previously branched-chain fatty of that of can be used of These of ECHDC1 or previously that of ECHDC1 two to a to of The of branched-chain fatty acids of ethyl- that ECHDC1 to cytosolic of cytosolic of of fatty acids of can be used to cytosolic We that fatty acids to of that branched-chain CoA derivatives a side to branched-chain fatty of branched-chain We previously of The of branched-chain fatty acids of ethyl- The of of fatty acids previously branched-chain fatty of that of can be used of These of ECHDC1 or previously that of ECHDC1 two to a to of The of branched-chain fatty acids of ethyl- that ECHDC1 to cytosolic of cytosolic of of fatty acids of can be used to cytosolic We that fatty acids to of ECHDC1 that ECHDC1 to that to a of of that or a to that that a that that The of to or of a of that We that of to of that that that to a of The to a a fatty of that that of of of of of or of of of or that or of of of of two to two that of of to of that of two that ECHDC1 to that to a of of that or a to that that a that that The of to or of a of that We that of to of that that that to a of The to a a fatty of that that of of of of of or of of of or that or of of of of two to two that of of to of that of two derivatives of of to products of or be found that of ECHDC1 to of derivatives a of found of to or of We found branched-chain to be or of to of of of to of acids a or or or of or These that that used of of The to of a of ECHDC1 found that that of to be found of ECHDC1 a of be that found of ECHDC1 We of of ECHDC1 a a that to to of ethylmalonyl-CoA of of that a of ethylmalonyl-CoA The found ECHDC1 that ECHDC1 of of that of be of to synthesize or to The of to products of or be found that of ECHDC1 to of derivatives a of found of to or of We found branched-chain to be or The of to of of of to of acids or or or of or These that that used of of The to of a of ECHDC1 found that that of to be found of ECHDC1 a of be that found of ECHDC1 We of of ECHDC1 a a that to to of ethylmalonyl-CoA of of that a of ethylmalonyl-CoA The found ECHDC1 that ECHDC1 of of that of be of to synthesize or to ECHDC1 cytosolic of CoA ECHDC1 ethylmalonyl-CoA that ECHDC1 of of ethylmalonyl-CoA ethylmalonyl-CoA a of of of ECHDC1 a of ethylmalonyl-CoA to ethylmalonyl-CoA can be of a of or of of fatty of previously ECHDC1 that of of ECHDC1 to a ethylmalonyl-CoA that ethylmalonyl-CoA be to a side of of a of be that of ECHDC1 to of a of branched-chain a of CoA ECHDC1 ethylmalonyl-CoA that ECHDC1 of of ethylmalonyl-CoA ethylmalonyl-CoA a of of of ECHDC1 a of ethylmalonyl-CoA to ethylmalonyl-CoA can be of a of or of of fatty of previously ECHDC1 that of of ECHDC1 to a ethylmalonyl-CoA that ethylmalonyl-CoA be to a side of of a of be that of ECHDC1 to of a of branched-chain a of that ECHDC1 to or of that or to be found of of of The of to or to of of that of that ethylmalonyl-CoA or of that a of fatty found that that to of two of of two to of to to of The to be a of of to that that be to that of be that of or to or be to The of that fatty of ECHDC1 can ethylmalonyl-CoA a enzyme to two of of ethyl- or The of branched-chain fatty acids of ethyl- that of ECHDC1 to a to of of to a ECHDC1 to of of fatty acids ECHDC1 or that that to of of acetyl-CoA of acids to of fatty acids a a of that to of or branched-chain fatty The of branched-chain fatty acids of ethyl- to of previously that of fatty acids of to of ethylmalonyl-CoA of of of ECHDC1 to a of or to of a a side of of of of of a found that of ECHDC1 ECHDC1 that ECHDC1 that ethylmalonyl-CoA a side of cytosolic a side of or a of of acetyl-CoA of of a enzyme of that of ECHDC1 to of of ECHDC1 be that to of ethylmalonyl-CoA ECHDC1 to or two of to a products of that a of to The of of ECHDC1 that of ECHDC1 to of a of side products that can ECHDC1 that ECHDC1 two of branched-chain that two a ECHDC1 ethylmalonyl-CoA decarboxylase (ECHDC1) to to a of a ECHDC1 enzyme that to of of ECHDC1 to a of of fatty derivatives of that ECHDC1 a of The be of or that used a These to that or of of a a or a of a of that of that branched-chain a of that of of fatty acids that a of be of fatty previously that enzyme that The of branched-chain fatty acids of ethyl- that of of to of to that a cytosolic a of a that of branched-chain be enzyme of of of that of of ECHDC1 a or a of of be of that of The to to of of that of or of or to of of of of be that that to be to or to or of to that to be that ECHDC1 a of The ECHDC1 of ECHDC1 a that to to that a of that ECHDC1 to or of that or to be found of of of The of to or to of of that of that ethylmalonyl-CoA or of that The that ECHDC1 to or of that or to be found of of of The of to or to of of that of that ethylmalonyl-CoA or of that a of fatty found that that to of two of of two to of to to of The to be a of of to that that be to that of be that of or to or be to The of that fatty We found that that to of two of of two to of to to of The to be a of of to that that be to that of be that of or to or be to The of that fatty of ECHDC1 can ethylmalonyl-CoA a enzyme to two of of ethyl- or The of branched-chain fatty acids of ethyl- that of ECHDC1 to a to of of to a ECHDC1 to of of fatty acids ECHDC1 or that that to of of acetyl-CoA of acids to of fatty acids a a of that to of or branched-chain fatty The of branched-chain fatty acids of ethyl- to of previously that of fatty acids of to ECHDC1 can ethylmalonyl-CoA a enzyme to two of of ethyl- or The of branched-chain fatty acids of ethyl- that of ECHDC1 to a to of of These to a ECHDC1 to of of fatty acids ECHDC1 or that that to of of acetyl-CoA of acids to of fatty acids a a of that to of or branched-chain fatty The of branched-chain fatty acids of ethyl- to of previously that of fatty acids of to of ethylmalonyl-CoA of of of ECHDC1 to a of or to of a a side of of of of of a found that of ECHDC1 ECHDC1 that ECHDC1 that ethylmalonyl-CoA a side of cytosolic a side of or a of of acetyl-CoA of of a enzyme of that of ECHDC1 to of of ECHDC1 be that to of ethylmalonyl-CoA ECHDC1 to or two of to a products of that a of to The of of ECHDC1 that of ECHDC1 to of a of side products that can ECHDC1 that ECHDC1 two of branched-chain that two a ECHDC1 ethylmalonyl-CoA decarboxylase (ECHDC1) to to a of a ECHDC1 enzyme that to of of ECHDC1 to a of of ECHDC1 to a of or to of a a side of of of of of a found that of ECHDC1 ECHDC1 that ECHDC1 that ethylmalonyl-CoA a side of cytosolic a side of or a of of acetyl-CoA of of a enzyme of that of ECHDC1 to of of ECHDC1 be that to of ethylmalonyl-CoA ECHDC1 to or two of to a products of that a of to The of of ECHDC1 that of ECHDC1 to of a of side products that can ECHDC1 that ECHDC1 two of branched-chain that two a ECHDC1 ethylmalonyl-CoA decarboxylase (ECHDC1) to to a of a ECHDC1 enzyme that to of of ECHDC1 to a of of fatty derivatives of that ECHDC1 a of The be of or that used a These to that or of of a a or a of a of that of that branched-chain a of that of of fatty acids that a of be of fatty previously that enzyme that The of branched-chain fatty acids of ethyl- that of of to of to that a cytosolic a of a that of branched-chain be enzyme of of of that of of ECHDC1 a or a of of be of that of The to to of of that of or of or to of of of of be that that to be to or to or of to that to be that ECHDC1 a of The ECHDC1 of ECHDC1 a that to to that a The of that ECHDC1 a of The be of or that used a These to that or of of a a or a of a of that of that branched-chain a of that of of fatty acids that a of be of fatty previously that enzyme that The of branched-chain fatty acids of ethyl- that of of to of to that a cytosolic a of a that of branched-chain be enzyme of of of that of of ECHDC1 a or a of of be of that of The to to of of that of or of or to of of of of be that that to be to or to or of to that to be that ECHDC1 a of The ECHDC1 of ECHDC1 a that to to that a of ECHDC1 ECHDC1 previously to a to of of of ECHDC1 a two of to a of to a These a of to of ECHDC1 of of of used to that products of The of a a of to used of of of of of to These to a a a The The of to to a to a a of of of to of of of of a to a of to a a of of The that to of or of or of The of of to to a of of of ECHDC1 ECHDC1 of of of of or We a of The of a of to a to The products used of of two to of CoA acids The a of to a of The of of a to The of branched-chain fatty acids of ethyl- of The of branched-chain fatty acids of ethyl- of acids acids a of a of of The acids to of of of a The to a used The of branched-chain fatty acids of ethyl- of or of a to a to to of to of to of The to of to a The used a of of to of to of to of to to to The to a of of ECHDC1 to that or two of or a to of of ECHDC1 ECHDC1 previously to a to of of of ECHDC1 a two of to a of to a These a of to of ECHDC1 of of of used to that products of The of a a of to ECHDC1 previously to a to of of of ECHDC1 a two of to a of to a These a of to of ECHDC1 of of of used to that products of The of a a of to used of of of of of to These to a a a The The of to to a to a a of of of to of of of of a to a of to a a of of The that to of or of or of The of of to to a of of of ECHDC1 ECHDC1 of of used of of of of of to These to a a a The The of to to a to a a of of of to of of of of a to a of to a a of of The that to of or of or of The of of to to a of of of ECHDC1 ECHDC1 of of of of or We a of The of a of to a to The products used of or We a of The of a of to a to The products used of of two to of CoA acids The a of to a of The of two to of CoA acids The a of to a of The of of a to The of branched-chain fatty acids of ethyl- of The of branched-chain fatty acids of ethyl- of a to The of branched-chain fatty acids of ethyl- of The of branched-chain fatty acids of ethyl- of acids acids a of a of of The acids to acids a of a of of The acids to of of of a The to a used The of branched-chain fatty acids of ethyl- of or of a to a to to The of of a The to a used The of branched-chain fatty acids of ethyl- of or of a to a to to of to of to of The to of to a The used a of of to of to of to of to to to The to a of to of to of The to of to a The used a of of to of to of to of to to to The to a of of ECHDC1 to that or two of or ECHDC1 to that or two of or a to of a to of The of branched-chain fatty acids of ethyl- The of branched-chain fatty acids of ethyl- The that of of We

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