Polyunsaturated fatty acyl-coenzyme As are inhibitors of cholesterol biosynthesis in zebrafish and mice.
Polyunsaturated fatty acyl-coenzyme As are inhibitors of cholesterol biosynthesis in zebrafish and mice.
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DOI：
10.1242/dmm.013425
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发表时间：
2013-11
影响因子：
4.3
通讯作者：
Schlegel A
中科院分区：
文献类型：
--
作者：
Karanth S;Tran VM;Kuberan B;Schlegel A
血脂紊乱对治疗构成了挑战。此前，我们发现斑马鱼肝细胞β-羟丁酸转运体SLC16a6a的突变会导致禁食期间肝脏脂肪变性，表现为肝脏三酰甘油升高，而不是胆固醇。这种捕获的生酮碳原子的选择性转移令人惊讶，因为醋酸盐和乙酰乙酸酯可以离开线粒体，并可以并入正常肝细胞中的脂肪酸和胆固醇中。为了阐明这种碳原子向脂肪酸选择性转移的机制，我们给野生型和slc16a6a突变动物喂以高蛋白生酮饲料。我们发现，slc16a6a突变体降低了胆固醇生物合成限速酶3-羟基-3-甲基戊二酰辅酶A还原酶(Hmgcr)的活性，尽管Hmgcr蛋白丰度增加，甲氧戊酸相对掺入胆固醇中。这些观察表明存在内源性Hmgcr抑制物。我们采取了一种候选的方法来鉴定这种抑制剂。首先，我们发现突变的肝脏积累了多种多不饱和脂肪酸(PUFAs)和PUFA-COAS，并且我们发现PUFA-COAS在体外对人HMGCR有抑制作用。其次，我们给小鼠注射了PUFA二十碳五烯酸乙酯，观察到肝脏Hmgcr活性急剧下降，而Hmgcr蛋白丰度没有变化。这些结果阐明了多不饱和脂肪酸通过直接抑制Hmgcr来降低胆固醇的机制。
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.
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影响因子：
4.5
作者：
Bertrand S;Thisse B;Tavares R;Sachs L;Chaumot A;Bardet PL;Escrivà H;Duffraisse M;Marchand O;Safi R;Thisse C;Laudet V
通讯作者：
Laudet V
影响因子：
2
作者：
Du, CY;Sato, A;Okuyama, H
通讯作者：
Okuyama, H
DOI：
10.1016/0005-2760(77)90004-2
发表时间：
1977-01-01
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
FAAS, FH;CARTER, WJ;WYNN, JO
通讯作者：
WYNN, JO
影响因子：
7.1
作者：
BANG, HO;DYERBERG, J;SINCLAIR, HM
通讯作者：
SINCLAIR, HM
影响因子：
3.9
作者：
Brownsey, RW;Boone, AN;Lee, WM
通讯作者：
Lee, WM