1. Academic Validation
  2. NPY stimulates cholesterol synthesis acutely by activating the SREBP2-HMGCR pathway through the Y1 and Y5 receptors in murine hepatocytes

NPY stimulates cholesterol synthesis acutely by activating the SREBP2-HMGCR pathway through the Y1 and Y5 receptors in murine hepatocytes

  • Life Sci. 2020 Dec 1;262:118478. doi: 10.1016/j.lfs.2020.118478.
Fu Chen 1 Yong Zhou 1 Keyu Yang 1 Mingyang Shen 1 Yong Wang 2
Affiliations

Affiliations

  • 1 Department of General Surgery, Fourth Affiliated Hospital of China Medical University, No. 4, Chongshan East Road, Huanggu District, Shenyang City, Liaoning Province 110032, China.
  • 2 Department of General Surgery, Fourth Affiliated Hospital of China Medical University, No. 4, Chongshan East Road, Huanggu District, Shenyang City, Liaoning Province 110032, China. Electronic address: wangyong@cmu.edu.cn.
Abstract

Aims: The development of non-alcoholic fatty liver disease (NAFLD) is partially attributed to disturbance in Cholesterol metabolism and sympathetic overactivity. Excessive levels of the sympathetic neurotransmitter neuropeptide Y (NPY) positively correlated with both NAFLD and Cholesterol accumulation. We wanted to determine, for the first time, whether NPY promotes Cholesterol accumulation directly in hepatocytes and elucidate the underlying mechanism.

Main methods: In vivo, NPY was injected through the hepatic portal vein into SD rats. One hour later, serum and liver tissues were collected. In vitro, BRL-3A hepatocytes were treated with NPY, and with Y1, Y2, Y5, receptor antagonists as well as with extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) antagonist, respectively. Cholesterol content was measured by coupled Enzyme method. Precursor sterol-regulatory element binding protein 2 (pSREBP2), mature SREBP2 (mSREBP2), HMG-CoA reductase (HMGCR), ERK1/2, pERK1/2, cAMP-dependent protein kinase (PKA), and pPKA protein expression levels were examined by western blotting.

Key findings: In rats, intraportal vein injection of NPY activates pSREBP2, mSREBP2, and HMGCR protein expression, and induces hepatic Cholesterol accumulation. In BRL-3A cells, we observed that NPY increases cholesterogenic protein expression and Cholesterol synthesis through Y1 and Y5 receptors. This effect is mediated by the activation of the ERK1/2 signaling pathway.

Significance: We demonstrated, for the first time, that NPY can activate the cholesterogenic pathway and elucidated the underlying mechanism. Thus, NPY and NPY receptors might be new targets for the treatment of NAFLD and dyslipidemia.

Keywords

Cholesterol; Dyslipidemia; NAFLD; NPY; Sympathetic nerve.

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