Section on Islet Cell and Regenerative Biology, Research Division, Joslin Diabetes Center, Boston, MA, USA.
Department of Genetics, Harvard Medical School, Boston, MA, USA.
Sci Adv. 2023 Jan 4;9(1):eadc8917. doi: 10.1126/sciadv.adc8917.
Although excessive lipid accumulation is a hallmark of obesity-related pathologies, some lipids are beneficial. Oleic acid (OA), the most abundant monounsaturated fatty acid (FA), promotes health and longevity. Here, we show that OA benefits by activating the endoplasmic reticulum (ER)-resident transcription factor SKN-1A (Nrf1/NFE2L1) in a lipid homeostasis response. SKN-1A/Nrf1 is cleared from the ER by the ER-associated degradation (ERAD) machinery and stabilized when proteasome activity is low and canonically maintains proteasome homeostasis. Unexpectedly, OA increases nuclear SKN-1A levels independently of proteasome activity, through lipid droplet-dependent enhancement of ERAD. In turn, SKN-1A reduces steatosis by reshaping the lipid metabolism transcriptome and mediates longevity from OA provided through endogenous accumulation, reduced H3K4 trimethylation, or dietary supplementation. Our findings reveal an unexpected mechanism of FA signal transduction, as well as a lipid homeostasis pathway that provides strategies for opposing steatosis and aging, and may mediate some benefits of the OA-rich Mediterranean diet.
虽然脂质过度积累是肥胖相关病理的一个标志，但有些脂质是有益的。油酸（OA）是最丰富的单不饱和脂肪酸（FA），它促进健康和长寿。在这里，我们表明，OA 通过激活内质网（ER）驻留转录因子 SKN-1A（Nrf1/NFE2L1）在脂质稳态反应中发挥作用。SKN-1A/Nrf1 被 ER 相关降解（ERAD）机制从 ER 中清除，并且在蛋白酶体活性低时稳定，并且通常维持蛋白酶体稳态。出乎意料的是，OA 通过脂滴依赖性增强 ERAD，独立于蛋白酶体活性增加核 SKN-1A 水平。反过来，SKN-1A 通过重塑脂质代谢转录组来减少脂肪变性，并通过内源性积累、减少 H3K4 三甲基化或饮食补充来介导 OA 提供的长寿。我们的发现揭示了 FA 信号转导的一种意外机制，以及一种脂质稳态途径，为对抗脂肪变性和衰老提供了策略，并可能介导富含 OA 的地中海饮食的一些益处。
