TRIF as a novel mediator of estrogen-regulated hepatic PCSK9 secretion

Professor Hoo, Ruby Lai Chong   (Principal Investigator (PI))

Professor Dorweiler Bernhard   (Co-Investigator)

Dr Lam Jenny Ka Wing   (Co-Investigator)

36

2021-01-01

996285

TRIF as a novel mediator of estrogen-regulated hepatic PCSK9 secretion

Atherosclerosis, Estrogen, LDL receptor, PCSK9, TRIF

Molecular BiologyCardiovascular Research

Biology and Medicine (M)

17102920

General Research Fund (GRF)

2020

Completed

1 To validate that TRIF regulates circulating PCSK9 in gender-specific manner using tissue-specific knockout mice: We observed an increase in LDL levels and aortic lesions in female but not male TRIF-deficient atherogenic mice. In addition, a higher hepatic PCSK expression was detected in female global TRIF-knockout mice compared with wild type, and no difference was observed in male. We will first validate that the gender-specific effect on PCSK9 is mediated by the TRIF in liver. 2 To explore the molecular mechanism of how TRIF regulates estrogen-inhibited PCSK9 secretion in hepatocytes: Although PCSK monoclonal antibody is available in the market for treating hypercholesterolemia, the molecular regulation of PCSK9 secretion remains unclear. We demonstrated that estrogen treatment inhibited extracellular but not intracellular PSCK9 expressions in wild type hepatocytes, and the extracellular PCSK9 level was oppositely induced by estrogen in TRIF-deficient cells. In this part of study, we will investigate the underlying mechanism. 3 To investigate whether poly-I:C treatment inhibits PCSK9 secretion in ovariectomized female and male mice: Our in vitro data showed that polyinosinic:polycytidylic acid (poly-I:C) treatment can inhibit PCSK9 secretion in female hepatocytes in TRIF-dependent manner. We will examine the feasibility of using such small molecule to inhibit PCSK9 and eventually upregulate LDL receptor and decrease LDL level in vivo. The current anti-PCSK9 therapy using monoclonal antibody is expensive, and the use of small molecule targeting PCSK9 is noteworthy to investigate.