Diabetes:高浓度硬脂酸导致胰岛素抵抗

哈尔滨医科大学的科研人员近期发现，高浓度硬脂酸能够导致胰岛素抵抗。相关研究成果发表在最新一期的美国糖尿病学会会刊《糖尿病》杂志上。

据介绍，高脂血症是由于体内脂质代谢紊乱引起的、以一种或多种血浆脂质成分浓度异常升高为特征的病症。研究表明，高脂血症与胰岛素抵抗、Ⅱ型糖尿病有着密切的关系。而血清脂肪酸谱的变化能更好地反应胰岛素抵抗及糖尿病的发生发展并揭示其潜在机制，因此越来越受到研究者的关注。

不过，目前对于血清脂肪酸谱在高脂血症中的研究均集中于空腹状态，对其在餐后状态下的研究探讨仍处于空白阶段。众所周知，一日三餐，机体大多数时间处于餐后状态，因此研究餐后血清脂肪酸谱及其代谢的变化对机体的影响更具有实际意义。

哈尔滨医科大学公共卫生学院的青年教师初霞、刘丽燕在孙长颢、李颖教授的指导下，通过对高脂血症人群餐后血清脂肪酸谱变化的研究，首次发现仅有一种脂肪酸——硬脂酸在餐后状态时水平显著增高，高浓度硬脂酸能够导致胰岛素抵抗，而降低SREBP-1c表达能够降低硬脂酸水平，进而改善胰岛素抵抗。

研究人员对高脂血症人群餐后血清硬脂酸水平升高的分子机制、高浓度硬脂酸对胰岛素抵抗方面的影响以及如何降低餐后升高的硬脂酸水平进行了深入系统的研究，最终发现增高的硬脂酸是由于餐后血清胰岛素浓度的升高刺激了硬脂酸的从头合成及软脂酸的直接延长（ELOVL6）。通过体内、体外的小RNA干扰技术，研究人员证实降低SREBP-1c或ELOVL6的表达均能降低硬脂酸水平，进而改善胰岛素抵抗。在进一步比较了干扰两靶点后的差异，他们发现，抑制SREBP-1c表达能够更加有效地改善胰岛素抵抗。

相关专家认为，这一发现为改善高脂血症人群出现的胰岛素抵抗，预防糖尿病的发生提供了新靶点、新思路。

相关研究得到国家自然科学基金重点项目和国家“863”计划项目的支持。

doi: 10.2337/db12-0139

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Sterol Regulatory Element–Binding Protein-1c Mediates Increase of Postprandial Stearic Acid, Potential Target for Improving Insulin Resistance, in Hyperlipidemia

Xia Chu, Liyan Liu, Lixin Na, Huimin Lu, Songtao Li, Ying Li and Changhao Sun

Elevated serum free fatty acids (FFAs) levels play an important role in the development of insulin resistance (IR) and diabetes. We investigated the dynamic changes and the underlying regulatory mechanism of postprandial FFA profile in hyperlipidemia (HLP) and their relation with insulin sensitivity in both humans and mice. We found that serum stearic acid (SA) is the only fatty acid that is increased dramatically in the postprandial state. The elevation of SA is due to increased insulin-stimulated de novo synthesis mediated by sterol regulatory element–binding protein-1c (SREBP-1c)/acetyl-CoA carboxylase/fatty acid synthase/elongation of long-chain fatty acid family member 6 (ELOVL6) and the elongation of palmitic acid (PA) catalyzed by ELOVL6. Downregulation of SREBP-1c or ELOVL6 by small interfering RNA can reduce SA synthesis in liver and serum SA level, followed by amelioration of IR in HLP mice. However, inhibition of SREBP-1c is more effective in improving IR than suppression of ELOVL6, which resulted in accumulation of PA. In summary, increased postprandial SA is caused by the insulin-stimulated SREBP-1c pathway and elongation of PA in HLP. Reduction of postprandial SA is a good candidate for improving IR, and SREBP-1c is potentially a better target to prevent IR and diabetes by decreasing SA.