4,4-Dimethylsterols Reduces Fat Accumulation via Inhibiting Fatty Acid Amide Hydrolase In Vitro and In Vivo  

作　　者：Tao Zhang Liangliang Xie Yiwen Guo Zhangtie Wang Xin Guo Ruijie Liu Qingzhe Jin Ming Chang Xingguo Wang 

机构地区：[1]School of Food Science and Technology,State Key Laboratory of Food Science and Technology,Jiangnan University,Wuxi 214122,China [2]College of Food Science and Technology,Huazhong Agricultural University,Wuhan 430070,China [3]School of Biological and Food Engineering,Anhui Polytechnic University,Wuhu 241000,China [4]College of Biosystems Engineering and Food Science,Zhejiang University,Hangzhou 310058,China [5]Department of Food Science,University of Massachusetts Amherst,Amherst,MA 01003,USA.

出　　处：《Research》2025年第1期280-291,共12页研究(英文)

基　　金：support from the National Natural Science Foundation of China(no.32272302);the Jiangsu Province Key National Industry Technology Research and Development Cooperation Project(BZ2022041).

摘　　要：4,4-Dimethylsterols constitute a unique class of phytosterols responsible for regulating endogenous cannabinoid system(ECS)functions.However,precise mechanism through which 4,4-dimethylsterols affect fat metabolism and the linkage to the ECS remain unresolved.In this study,we identified that 4,4-dimethylsterols,distinct from 4-demethseterols,act as inhibitors of fatty acid amide hydrolases(FAAHs)both in vivo and in vitro.Genetic ablation of FAAHs(faah-1)abolishes the effects of 4,4-dimethylsterols on fat accumulation and locomotion behavior in a Caenorhabditis elegans model.We confirmed that dietary intervention with 4,4-dimethylsterols in a high-fat diet(HFD)mouse model leads to a significant reduction in body weight(>11.28%)with improved lipid profiles in the liver and adipose tissues and increased fecal triacylglycerol excretion.Untargeted and targeted metabolomics further verified that 4,4-dimethylsterols influence unsaturated fatty acid biosynthesis and elevate oleoyl ethanolamine levels in the intestine.We propose a potential molecular mechanism in which 4,4-dimethylsterols engage in binding interactions with the catalytic pocket(Ser241)of FAAH-1 protein due to the shielded polarity,arising from the presence of 2 additional methyl groups(CH3).Consequently,4,4-dimethylsterols represent an unexplored class of beneficial phytosterols that coordinate with FAAH-1 activity to reduce fat accumulation,which offers new insight into intervention strategies for treating diet-induced obesity.

关 键 词：dimethylsterols fatty acid amide hydrolase lipid profiles high fat diet fat metabolism endogenous cannabinoid system fatty acid amide hydrolases faahs both 

分 类 号：R285[医药卫生—中药学] R151.3[医药卫生—中医学]