Paradoxical feeding activation of gut lipophagy by FGF15/FGF19-NR0B2/SHP-TFEB

Macroautophagic/autophagic degradation of lipid droplets, lipophagy, is activated by fasting but repressed by feeding. Surprisingly, our recent study showed that this is not the case in the gut, where feeding activates lipophagy, reducing intestinal lipid levels. Transgenic mouse studies revealed that feeding activation of gut lipophagy requires both FGF15/FGF19 (fibroblast growth factor 15/fibroblast growth factor 19) and an orphan nuclear receptor, NR0B2/SHP (nuclear receptor subfamily 0, group B, member 2). Mechanistically, feeding-induced FGF15/FGF19 activates intestinal PRKC/PKC signaling, which in turn phosphorylates NR0B2 and the autophagic activator TFEB (transcription factor EB), leading to their nuclear localization and transcriptional induction of lipophagy network genes, including Ulk1 and Pnpla2/Atgl. Given that an essential function of the gut is to distribute dietary lipids throughout the body, this study identifies a physiologically important homeostatic mechanism to maintain healthy lipid levels. The intestinal FGF15/FGF19-NR0B2/SHP-TFEB pathway that regulates postprandial lipids by lipophagic activation, thus, may provide novel targets for treating dyslipidemia and obesity.