Diminished hepatic gluconeogenesis via defects in tricarboxylic acid cycle flux in peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α)-deficient mice
Diminished hepatic gluconeogenesis via defects in tricarboxylic acid cycle flux in peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α)-deficient mice
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DOI：
10.1074/jbc.m600050200
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发表时间：
2006-07-14
影响因子：
4.8
通讯作者：
Finck, Brian N.
中科院分区：
文献类型：
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作者：
Burgess, Shawn C.;Leone, Teresa C.;Finck, Brian N.
过氧化物酶体增殖物激活受体γ（PPAR γ）辅激活因子1 α（PGC-1 α）是一种高度诱导的转录辅激活因子，参与肝脂肪酸氧化、氧化磷酸化和肝细胞生成相关酶的基因编码的协调调节。本研究旨在评估慢性PGC-1 α缺乏对通过肝促炎、脂肪酸氧化和三羧酸循环途径的代谢通量的影响。为此，使用基于同位素的NMR和互补基因表达分析评估了野生型（WT）和PGC-1 α（-/-）小鼠的肝脏代谢。在PGC-1 α（-/-）肝脏中，肝脏葡萄糖产生减少，与磷酸烯醇丙酮酸的产酸通量减少一致。令人惊讶的是，在进食和禁食条件下，与WT小鼠相比，PGC-1 α（-/-）中参与胚胎发生的PGC-1 α靶基因的表达没有改变。在PGC-1 α-/-肝脏中，通过三羧酸循环和线粒体脂肪酸β-氧化途径的通量也减少。在PGC-1 α（-/-）小鼠中，编码三羧酸循环和氧化磷酸化酶的多个基因的表达被显著抑制，并且在WT小鼠的肝脏中被PGC-1 α过表达激活。总的来说，这些研究结果表明，慢性全动物PGC-1 α缺乏导致肝脏葡萄糖生成缺陷，继发于脂肪酸β-氧化和三羧酸循环通量减少，而不是生精酶基因表达本身异常。
The peroxisome proliferator-activated receptor gamma(PPAR gamma) coactivator 1 alpha(PGC-1 alpha) is a highly inducible transcriptional coactivator implicated in the coordinate regulation of genes encoding enzymes involved in hepatic fatty acid oxidation, oxidative phosphorylation, and gluconeogenesis. The present study sought to assess the effects of chronic PGC-1 alpha deficiency on metabolic flux through the hepatic gluconeogenic, fatty acid oxidation, and tricarboxylic acid cycle pathways. To this end, hepatic metabolism was assessed in wild-type (WT) and PGC-1 alpha(-/-) mice using isotopomer-based NMR with complementary gene expression analyses. Hepatic glucose production was diminished in PGC-1 alpha(-/-) livers coincident with reduced gluconeogenic flux from phosphoenolpyruvate. Surprisingly, the expression of PGC-1 alpha target genes involved in gluconeogenesis was unaltered in PGC-1 alpha(-/-) compared withWTmice under fed and fasted conditions. Flux through tricarboxylic acid cycle and mitochondrial fatty acid beta-oxidation pathways was also diminished in PGC-1 alpha-/- livers. The expression of multiple genes encoding tricarboxylic acid cycle and oxidative phosphorylation enzymes was significantly depressed in PGC-1 alpha(-/-) mice and was activated by PGC-1 alpha overexpression in the livers of WT mice. Collectively, these findings suggest that chronic wholeanimal PGC-1 alpha deficiency results in defects in hepatic glucose production that are secondary to diminished fatty acid beta-oxidation and tricarboxylic acid cycle flux rather than abnormalities in gluconeogenic enzyme gene expression per se.