Leptin decreases the expression of low-density lipoprotein receptor via PCSK9 pathway: linking dyslipidemia with obesity.
BACKGROUND
Previous studies have suggested that people with obesity showed elevated serum levels of leptin as well as lipid dysfunction and proprotein convertase subtilisin/kexin type 9 (PCSK9) played an important role in the regulation of lipid metabolism recently. The aim of this study was to determine if leptin participated in regulating the uptake of low-density lipoproteins (LDL) in hepatocytes via PCSK9.


METHODS
HepG2 cells were treated with human recombinant leptin. The impact of leptin on cellular low density lipoprotein receptor (LDLR) and PCSK9 protein levels was determined by Western blot. Dil-LDL uptake assay was performed to examine the LDLR function. Specific small interfering RNAs (siRNAs) were used to interfere the expressions of target proteins.


RESULTS
The expression of LDLR and LDL uptake could be significantly down-regulated by leptin treatment while the expressions of PCSK9 and hepatocyte nuclear factor 1α (HNF1α) were enhanced in HepG2 cells. Furthermore, inhibition of PCSK9 or HNF1α expression by siRNAs rescued the reduction of LDLR expression and LDL uptake by leptin. We found that leptin activated the p38 mitogen-activated protein kinase (p38MAPK) signaling pathway. Moreover, the changes of the expressions of HNF1α, PCSK9, LDLR, and LDL uptake induced by leptin could be blocked by p38MAPK inhibitor (SB203580). Additionally, leptin attenuated the up-regulation of LDLR caused by atorvastatin in HepG2 cells.


CONCLUSIONS
These findings indicated firstly that leptin reduced LDLR levels in hepatocyte via PCSK9 pathway, suggesting that PCSK9 might be a alternative target for dyslipidemia in the obesity.
State Key Laboratory of Cardiovascular Disease, Division of Dyslipidemia, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, XiCheng District, Beijing, 100037, China.
Ying
Y
Du
State Key Laboratory of Cardiovascular Disease, Division of Dyslipidemia, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, XiCheng District, Beijing, 100037, China.
Sha
S
Li
State Key Laboratory of Cardiovascular Disease, Division of Dyslipidemia, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, XiCheng District, Beijing, 100037, China.
Chuan-Jue
CJ
Cui
State Key Laboratory of Cardiovascular Disease, Division of Dyslipidemia, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, XiCheng District, Beijing, 100037, China.
Yan
Y
Zhang
State Key Laboratory of Cardiovascular Disease, Division of Dyslipidemia, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, XiCheng District, Beijing, 100037, China.
Sheng-Hua
SH
Yang
State Key Laboratory of Cardiovascular Disease, Division of Dyslipidemia, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, XiCheng District, Beijing, 100037, China. lijianjun938@126.com.
Jian-Jun
JJ
Li
LDLR; Leptin; PCSK9
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