Rab30 regulates lipid homeostasis in the hepatocyte during fasting
In order to facilitate inter-tissue communication and exchange of proteins, lipoproteins, and metabolites with the circulation, hepatocytes have an intricate and efficient intracellular trafficking system regulated by small Rab GTPases.  Rab30, a putative Golgi-localized Rab GTPase, is induced in the mouse liver by fasting and its expression is further amplified in liver-specific carnitine palmitoyltransferase 2 knockout mice (Cpt2L-/-) that lack the ability to oxidize fatty acids in a Ppara-dependent manner.  Live-cell super-resolution imaging and biochemical in vivo proximity labeling demonstrated 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 and display intact Golgi ultrastructure. However, the loss of Rab30 in Rab30;Cpt2 DKO mice suppresses serum dyslipidemia observed in Cpt2L-/- single knockout mice.  Corresponding with decreased serum triglyceride and cholesterol levels, Rab30;Cpt2 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 Overall design: RNA-seq on whole livers was performed to investigate differentially regulated genes in 24hr fasted livers of Rab30 whole-body knockouts (KO) and their littermates ("WT littermate to Rab30 whole-body KO"), Rab30 liver-specific KO, Cpt2 liver-specific KO, Rab30;Cpt2 liver-specific double knockouts (DKO), and Rab30;Cpt2 floxed control (littermates to DKO) male mice. Liver-specific knockouts were generated by crossing floxed lines to and albumin-Cre transgenic mouse line.