p62/mTOR/LXRα pathway inhibits cholesterol efflux mediated by ABCA1 and ABCG1 during autophagy blockage.
OBJECTIVE
Atherosclerosis is a disease characterized by abnormal lipid metabolism, and the formation of foam cells is considered an early event of atherosclerosis. Intracellular cholesterol efflux mediated by ABCA1 and ABCG1 helps to reduce lipid accumulation in foam cells. Related studies have shown that autophagy and mTOR are involved in cholesterol efflux, but the role of p62, an autophagy substrate protein, has not been evaluated.


METHODS
THP-1 derived macrophages were incubated with ox-LDL to establish a foam cell model and treated with different autophagy inducers. The effects of p62 on cholesterol efflux were investigated using overexpression vectors, gene silencing and western blotting.


RESULTS
This study showed a blockage of autophagy and decreased expression of ABCA1 and ABCG1 under the stress of excess ox-LDL in a concentration-dependent manner in THP-1 cells. Furthermore, the activation of autophagy led to increased expression of ABCA1 and ABCG1, as well as their upstream transcription factor LXRα, thereby promoting cholesterol efflux from foam cells. We also demonstrated that accumulated p62 played an important role during autophagy blockage, which was achieved by activating mTOR and then inhibited the expression of LXRα and its downstream target proteins ABCA1 and ABCG1.


CONCLUSION
In conclusion, our experiments demonstrated that a p62/mTOR/LXRα signaling pathway was involved in cholesterol efflux mediated by ABCA1 and ABCG1 when autophagy blockage occurred. Our study offers a rationale for the development of autophagy and p62 as a new target for the treatment of atherosclerosis.
['Liang|Xiaofei|X|', 'Wang|Chao|C|', 'Sun|Yan|Y|', 'Song|Wei|W|', 'Lin|Jing|J|', 'Li|Jiashan|J|', 'Guan|Xiuru|X|']
D064286:ATP Binding Cassette Transporter 1 D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1 D000225:Adenine D001343:Autophagy D002784:Cholesterol D006801:Humans D000071518:Liver X Receptors D034741:RNA, Small Interfering D015398:Signal Transduction D000074084:THP-1 Cells D058570:TOR Serine-Threonine Kinases D051758:Transcription Factor TFIIH
mTOR LXRα Cholesterol efflux ABCA1 ABCG1 Autophagy Atherosclerosis p62/SQSTM1