Ganoderma Lucidum polysaccharide inhibits lipid accumulation in vivo and in vitro by activating HIF‐1a through ERK1/2 signaling pathway

Ganoderma lucidum polysaccharide (GLP) has been proposed to have beneficial effects against obesity. However, how GLP affects lipid accumulation has not been examined. In this study, we used 3T3‐L1 preadipocytes and a high‐fat diet‐induced obese mice model to investigate the effects and mechanism of GLP on lipid accumulation. Our results revealed that GLP significantly inhibited adipogenic differentiation in a dose‐dependent manner in 3T3‐L1 preadipocytes determined by Oil Red O staining and Triglyceride measurement. In order to explore the mechanism, we conducted a dynamic transcriptome study during 3T3‐L1 preadipocytes differentiation (0 h, 9 h, 18 h, 48 h, 120 h) with or without GLP treatment. Transcriptome analyses showed that GLP significantly caused cellular hypoxia by blocking respiration chain, and inducing the expression of HIF‐1a which is a major regulator of cell cycle arrest during hypoxia by activating the ERK1/2 signaling pathway. And then delayed the mitotic clonal expansion(MCE) which is required for differentiation of 3T3‐L1 cells, eventually inhibiting a cascade of adipogenesis pathway. These has been verified by qRT‐PCR or Western blot. Moreover, flow cytometry data revealed that GLP does arrest cell cycle at G0/G1 phase at 9 h of differentiation. Furthermore, knocking‐down of HIF‐1a by siRNA can abolish the GLP‐induced inhibition of adipogenesis in 3T3‐L1 cells, indicating that HIF‐1a was directly required for GLP‐induced inhibition of aidopogenesis. In addition, we demonstrated that GLP induces the phosphorylation of ERK1/2. Interestingly, pretreatment with ERK inhibitor, significantly rescued GLP‐induced inhibition of adipogenesis. We further demonstrated that HIF‐1a is the downstream target of ERK1/2. Furthermore, GLP treatment significantly suppressed hepatic lipid accumulation by activating ERK1/2/HIF‐1a signaling pathway to improve non‐alcoholic fatty liver disease(NAFLD) and insulin resistance in high‐fat diet‐induced obese mice. Taken together, GLP inhibits lipid accumulation by activating HIF‐1a through ERK1/2 signaling pathway in vivo and in vitro . These findings also indicate that GLP possesses protective effects in NAFLD and IR‐related metabolic disorders. Support or Funding Information National Natural Science Foundation of China (Grant No. 81473397). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .