Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Nat Commun. 2024 May 25;15(1):4469. doi: 10.1038/s41467-024-48959-x.
To facilitate inter-tissue communication and the exchange of proteins, lipoproteins, and metabolites with the circulation, hepatocytes have an intricate and efficient intracellular trafficking system regulated by small Rab GTPases. Here, we show that Rab30 is induced in the mouse liver by fasting, which is amplified in liver-specific carnitine palmitoyltransferase 2 knockout mice (Cpt2) lacking the ability to oxidize fatty acids, in a Pparα-dependent manner. Live-cell super-resolution imaging and in vivo proximity labeling demonstrates that Rab30-marked vesicles are highly dynamic and interact with proteins throughout the secretory pathway. Rab30 whole-body, liver-specific, and Rab30; Cpt2 liver-specific double knockout (DKO) mice are viable with intact Golgi ultrastructure, although Rab30 deficiency in DKO mice suppresses the serum dyslipidemia observed in Cpt2 mice. Corresponding with decreased serum triglyceride and cholesterol levels, DKO mice exhibit decreased circulating but not hepatic ApoA4 protein, indicative of a trafficking defect. Together, these data suggest a role for Rab30 in the selective sorting of lipoproteins to influence hepatocyte and circulating triglyceride levels, particularly during times of excessive lipid burden.
为了促进组织间的交流以及与循环系统之间蛋白质、脂蛋白和代谢物的交换，肝细胞具有一种复杂而高效的、受小分子 Rab GTPases 调控的细胞内运输系统。在这里，我们发现禁食会诱导小鼠肝脏中 Rab30 的产生，这种诱导在缺乏氧化脂肪酸能力的肝特异性肉毒碱棕榈酰基转移酶 2 敲除小鼠（Cpt2）中被放大，这一过程依赖于 Pparα。活细胞超分辨率成像和体内邻近标记表明，Rab30 标记的囊泡具有高度的动态性，并与整个分泌途径中的蛋白质相互作用。Rab30 全身敲除、肝特异性敲除和 Rab30; Cpt2 肝特异性双敲除（DKO）小鼠具有完整的高尔基超微结构，是有活力的，尽管 DKO 小鼠中 Rab30 的缺失抑制了 Cpt2 小鼠中观察到的血清血脂异常。与血清甘油三酯和胆固醇水平降低相对应，DKO 小鼠表现出循环但不是肝脏 ApoA4 蛋白的减少，表明存在运输缺陷。综上所述，这些数据表明 Rab30 在脂蛋白的选择性分拣中起作用，以影响肝细胞和循环甘油三酯水平，特别是在脂质负担过重时。
