Palmitoleic acid promoted by BMPR2 signaling primes CD169 macrophages and alleviates liver fibrosis.

Bone morphogenetic proteins (BMPs) participate in the energy metabolism. BMP receptor type 2 (BMPR2) is expressed in the liver. Whether BMPR2 is involved in the pathophysiology of nonalcoholic fatty liver disease (NAFLD) has not been studied. In this study, we analyzed the RNA-sequence data of several patient cohorts and found that BMPR2 expression decreases at the stages of advanced fibrosis. A mouse model featuring BMPR2 knockout demonstrate that BMPR2 knockout in the liver produces profibrotic effect upon long-term high-fat and high-fructose (HFF) diet challenge. BMP signaling promotes biosynthesis of unsaturated fatty acids, which is repressed under BMPR2 knockout condition. The most affected unsaturated fatty acid, palmitoleic acid (POA), is found to activate CD169 macrophages. Moreover, CD169 macrophages is revealed to have high levels of lysosomal enzyme along with matrix metalloproteinase 8, which degrades collagen and alleviates fibrosis. Our study demonstrates that BMPR2 influences over the progression of liver fibrosis induced by the HFF diet through fatty acid-regulated CD169 macrophages. POA-primed macrophages might be a potential therapeutic strategy for the treatment of liver fibrosis.