School of Public Health, Qingdao University, Qingdao, China.
School of Public Health, Qingdao University, Qingdao, China.
Biochem Pharmacol. 2024 Oct;228:115936. doi: 10.1016/j.bcp.2023.115936. Epub 2023 Nov 25.
Continuous (chronic or sub-chronic) alcohol consumption induces a metabolic byproduct known as ketone bodies, and the accumulation of ketones leads to a life-threatening syndrome called alcoholic ketoacidosis. However, the mechanism underlining the physiological effects of ketone accumulation in alcoholic liver disease (ALD) is still in its infancy. Here, we discovered that mitochondrial acetyl-CoA accumulation was diverted into the ketogenesis pathway in ethanol-fed mice and ethanol-exposed hepatocytes. Unexpectedly, global protein lysine β-hydroxybutyrylation (Kbhb) was induced in response to increased ketogenesis-derived β-hydroxybutyrate (BHB) levels both in hepatocytes and in livers of mice. Focusing on the solute carrier family (SLCs), we found that SLC25A5 presented obvious Kbhb at lysine residues 147 and 166. Kbhb modifications at these two lysine residues stabilized SLC25A5 expression by blocking ubiquitin-proteasome pathway. Subsequent mutation analysis revealed that Kbhb of SLC25A5 at K147 and K166 had site-specific regulatory roles by increasing peroxisome proliferator activated receptor gamma (PPARγ) expression, which further promoting lipogenesis. Additionally, 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 (HMGCS2), a rate-limiting enzyme for BHB production, was profoundly induced by ethanol exposure, and knockout of Hmgcs2 with CRISPR/Cas9 attenuated SLC25A5 Kbhb. Together, our study demonstrated a widespread Kbhb landscape under ethanol exposure and clarified a physiological effect of Kbhb modification on liver lipid accumulation.
持续（慢性或亚慢性）饮酒会导致一种称为酮体的代谢副产物产生，酮体的积累会导致一种危及生命的综合征，称为酒精性酮症酸中毒。然而，酮体积累在酒精性肝病（ALD）中的生理作用机制仍处于起步阶段。在这里，我们发现在乙醇喂养的小鼠和乙醇暴露的肝细胞中，线粒体乙酰辅酶 A 的积累被转移到酮生成途径中。出乎意料的是，在肝细胞和小鼠肝脏中，由于酮生成衍生的β-羟丁酸（BHB）水平增加，导致了全局蛋白赖氨酸β-羟丁酸化（Kbhb）的诱导。我们专注于溶质载体家族（SLCs），发现 SLC25A5 在赖氨酸残基 147 和 166 处明显存在 Kbhb。这两个赖氨酸残基上的 Kbhb 修饰通过阻止泛素-蛋白酶体途径稳定了 SLC25A5 的表达。随后的突变分析表明，SLC25A5 上 K147 和 K166 的 Kbhb 具有通过增加过氧化物酶体增殖物激活受体γ（PPARγ）表达来增加脂肪酸生成的特定调节作用。此外，HMGCS2（BHB 产生的限速酶）在乙醇暴露下被强烈诱导，并且通过 CRISPR/Cas9 敲除 Hmgcs2 减弱了 SLC25A5 的 Kbhb。总之，我们的研究表明在乙醇暴露下存在广泛的 Kbhb 图谱，并阐明了 Kbhb 修饰对肝脏脂质积累的生理作用。
