Ezetimibe ameliorates lipid accumulation during adipogenesis by regulating the AMPK–mTORC1 pathway

Abstract

Adipogenesis, a critical process that converts adipocyte precursors into adipocytes, is considered a potential therapeutic target for the treatment of obesity. Ezetimibe, a drug approved by the United States Food and Drug Administration, is used for the treatment of hypercholesterolemia. Recently, it was reported to ameliorate high fat diet‐induced dyslipidemia in mice and reduce lipid accumulation in hepatocytes through the activation of AMPK. However, the anti‐adipogenic effects of ezetimibe and the underlying molecular mechanism have not yet been elucidated. Here, we found that ezetimibe reduced lipid accumulation via activating AMPK during the early phase of adipogenesis. We also observed that ezetimibe inhibited peroxisome proliferator‐activated receptor γ, which is a major transcription factor of adipogenesis. Furthermore, ezetimibe‐mediated AMPK activation reduced lipid accumulation by inhibiting mTORC1 signaling, leading to the downregulation of lipogenesis‐related genes. Mitotic clonal expansion, required for adipogenesis, accelerates cell cycle progression and cell proliferation. We additionally observed that ezetimibe prevented the progression of mitotic clonal expansion by arresting the cell cycle at the G0/G1 phase, which was followed by the inhibition of cell proliferation. Collectively, ezetimibe‐mediated inhibition of adipogenesis is dependent on the AMPK–mTORC1 pathway. Thus, we suggest that ezetimibe might be a promising drug for the treatment of obesity.

Overexpression of cholinergic receptor nicotinic gamma subunit inhibits proliferation and differentiation of bovine preadipocytes

“…In livestock, the development of fat and muscle plays an important role in the formation of beef [ 17 ]. The process of preadipocyte proliferation and differentiation is the process of lipid accumulation [ 18 ]. This differentiation is the result of the synergistic effect of crucial transcription factors, especially PPARγ and C/EBPα [ 19 ].…”

Adipocyte-Specific Inhibition of Mir221/222 Ameliorates Diet-Induced Obesity Through Targeting Ddit4

“…Many researchers screened the agents or intrinsic factors to inhibit mTORC1 signaling and lipogenesis for the treatment of obesity. Lee et al reported that ezetimibe reduced lipid accumulation by inhibiting mTORC1 signaling, leading to the downregulation of lipogenesis-related genes (23). Shi et al reported that the inhibition of miR-196b-5p blocked adipogenesis and lipogenesis by directly targeting TSC1 and TGFBR1 (transforming growth factor-b receptor 1) (24).…”

“…Lee et al. reported that ezetimibe reduced lipid accumulation by inhibiting mTORC1 signaling, leading to the downregulation of lipogenesis-related genes ( 23 ). Shi et al.…”

MicroRNA-130a Is Elevated in Thyroid Eye Disease and Increases Lipid Accumulation in Fibroblasts Through the Suppression of AMPK

“…49 Nevertheless, metformin may be a promising drug that could be further tested in TED patients. Additionally, ezetimibe, a cholesterol-lowering drug, activates AMPK and reduces lipid accumulation during adipogenesis, 50 and it may be useful in treating TED. Taken together, our study shows for the first time, to our knowledge, that miR-130a is elevated in human OFs prone to adipogenesis and promotes lipid accumulation.…”