Alveolar type I cells can give rise to KRAS-induced lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer and presents clinically with a high degree of biological heterogeneity and distinct clinical outcomes. The current paradigm of LUAD etiology posits alveolar epithelial type II (AT2) cells as the primary cell of origin, while the role of AT1 cells in LUAD oncogenesis remains unknown. Here, we examine oncogenic transformation in mouse Gram-domain containing 2 (Gramd2)+ AT1 cells via oncogenic KRASG12D. Activation of KRASG12D in AT1 cells induces multifocal LUAD, primarily of papillary histology. Furthermore, KRT8+ intermediate cell states were observed in both AT2- and AT1-derived LUAD, but SCGB3A2+, another intermediate cell marker, was primarily associated with AT1 cells, suggesting different mechanisms of tumor evolution. Collectively, our study reveals that Gramd2+ AT1 cells can serve as a cell of origin for LUAD and suggests that distinct subtypes of LUAD based on cell of origin be considered in the development of therapeutics.

Dissociation of mercaptoacetate's effects on feeding and fat metabolism by dietary medium- and long-chain triacylglycerols in rats.

OBJECTIVE AND METHODS: Mercaptoacetate (MA) inhibits hepatic fatty acid oxidation (FAO) and stimulates feeding in rats fed fat-rich diets. To test whether the feeding stimulation by MA depends on hepatic FAO, we compared the effects of intraperitoneally injected MA (45.6 mg/kg body weight) with saline in rats fed diets containing 18% predominately long-chain triacylglycerols (LCTs; > or =90% 16 C) or 18% medium-chain triacylglycerols (MCTs; 51% 10-12 C). We hypothesized that, because medium-chain fatty acids reach the liver and are oxidized faster than long-chain fatty acids, if MA's feeding-stimulatory effect depends on hepatic FAO, MA should stimulate feeding more in MCT-fed rats than in LCT-fed rats. RESULTS: Although MA injected in mid-light phase stimulated feeding similarly in MCT- and LCT-fed rats, MA injected at light onset initially stimulated food intake (1 h) only in LCT- and not in MCT-fed rats. To investigate MA's metabolic effects during the initial hour, rats were sacrificed 30 min after light-onset injections. At this time plasma beta-hydroxybutyrate appeared to be higher in MCT- than in LCT-fed rats and to be increased by MA. In a final experiment, MA did not affect fatty acid content in liver and duodenum tissues but increased fatty acids in duodenal tissue mitochondria from 12 h-fasted rats fed chow. CONCLUSION: In light-onset tests, adaptation to the MCT diet increased hepatic FAO but not the feeding-stimulatory effect of MA in comparison with adaptation to the LCT diet, suggesting that at this time MA does not act in the liver to stimulate feeding or that this effect is not due to FAO inhibition. Inhibition of duodenal mitochondrial FAO may be another metabolic process through which MA stimulates feeding.

CPT1alpha over-expression increases long-chain fatty acid oxidation and reduces cell viability with incremental palmitic acid concentration in 293T cells.

To test the cellular response to an increased fatty acid oxidation, we generated a vector for an inducible expression of the rate-limiting enzyme carnitine palmitoyl-transferase 1alpha (CPT1alpha). Human embryonic 293T kidney cells were transiently transfected and expression of the CPT1alpha transgene in the tet-on vector was activated with doxycycline. Fatty acid oxidation was measured by determining the conversion of supplemented, synthetic cis-10-heptadecenoic acid (C17:1n-7) to C15:ln-7. CPT1alpha over-expression increased mitochondrial long-chain fatty acid oxidation about 6-fold. Addition of palmitic acid (PA) decreased viability of CPT1alpha over-expressing cells in a concentration-dependent manner. Both, PA and CPT1alpha over-expression increased cell death. Interestingly, PA reduced total cell number only in cells over-expressing CPT1alpha, suggesting an effect on cell proliferation that requires PA translocation across the mitochondrial inner membrane. This inducible expression system should be well suited to study the roles of CPT1 and fatty acid oxidation in lipotoxicity and metabolism in vivo.