Feeding activates FGF15‐SHP‐TFEB‐mediated lipophagy in the gut

Lysosome‐mediated macroautophagy, including lipophagy, is activated under nutrient deprivation but is repressed after feeding. We show that, unexpectedly, feeding activates intestinal autophagy/lipophagy in a manner dependent on both the orphan nuclear receptor, small heterodimer partner (SHP/NR0B2), and the gut hormone, fibroblast growth factor‐15/19 (FGF15/19). Furthermore, postprandial intestinal triglycerides (TGs) and apolipoprotein‐B48 (ApoB48), the TG‐rich chylomicron marker, were elevated in SHP‐knockout and FGF15‐knockout mice. Genomic analyses of the mouse intestine indicated that SHP partners with the key lysosomal activator, transcription factor‐EB (TFEB) to upregulate the transcription of autophagy/lipolysis network genes after feeding. FGF19 treatment activated lipophagy, reducing TG and ApoB48 levels in HT29 intestinal cells, which was dependent on TFEB. Mechanistically, feeding‐induced FGF15/19 signaling increased the nuclear localization of TFEB and SHP via PKC beta/zeta‐mediated phosphorylation, leading to increased transcription of the TFEB/SHP target lipophagy genes, Ulk1 and Atgl. Collectively, these results demonstrate that paradoxically after feeding, FGF15/19‐activated SHP and TFEB activate gut lipophagy, limiting postprandial TGs. As excess postprandial lipids cause dyslipidemia and obesity, the FGF15/19‐SHP‐TFEB axis that reduces intestinal TGs via lipophagic activation provides promising therapeutic targets for obesity‐associated metabolic disease.