Department of Cardiovascular Science, University of Sheffield, Sheffield, UK.
Curr Opin Lipidol. 2012 Apr;23(2):122-6. doi: 10.1097/MOL.0b013e3283508c3b.
The success of high throughput sequencing programmes, including the Human Genome Project led to the 'identification' of a large number of novel genes of completely unknown function. Since then, many of these genes have been subject to functional studies focussed on uncovering their biological importance. Recent advances in genome-wide screening of DNA sequence variants as well as focussed genetic studies identified a number of candidate loci contributing to the development of complex diseases, including those affecting lipid homeostasis. An excellent example for the convergence of genetics and experimental biology is the tribbles gene family which was among those identified both in recent genetic studies and were implicated in dysregulation of lipid levels experimentally. Thus, there is a need now to take a step back and reconcile these findings accumulated over recent years.
Allelic variants of tribbles proteins have been associated with the control of fatty acid synthesis and insulin resistance as well as regulating plasma triglyceride and HDL cholesterol levels. Several mechanisms of molecular action have been proposed for the tribbles mediated control of these processes, including the regulation of signalling events, protein turnover and transcription, sometimes with conflicting evidence emerging.
This review attempts to synthesize knowledge obtained on the biology of the tribbles protein family in the context of lipid metabolism as well as discussing the recently emerging genetic evidence for the importance of these proteins in human disease.
高通量测序项目的成功，包括人类基因组计划，导致了大量完全未知功能的新基因的“发现”。从那时起，许多这些基因已经成为了功能研究的对象，旨在揭示它们的生物学重要性。最近在全基因组范围内筛选 DNA 序列变异以及有针对性的遗传研究确定了一些候选基因座，这些基因座有助于复杂疾病的发展，包括那些影响脂质稳态的疾病。遗传学和实验生物学融合的一个很好的例子是 tribbles 基因家族，它是最近的遗传研究中发现的，并在实验中被认为与脂质水平的失调有关。因此，现在需要退一步，调和这些近年来积累的发现。
tribbles 蛋白的等位基因变异与脂肪酸合成和胰岛素抵抗的控制以及调节血浆甘油三酯和高密度脂蛋白胆固醇水平有关。已经提出了几种 tribbles 介导这些过程的分子作用机制，包括信号事件、蛋白质周转和转录的调节，有时会出现相互矛盾的证据。
本文综述试图在脂质代谢的背景下综合 tribbles 蛋白家族的生物学知识，并讨论最近出现的遗传证据，证明这些蛋白在人类疾病中的重要性。
