Research

We study metabolism and human diseases that are linked to it, such as atherosclerotic cardiovascular disease, non-alcohol fatty liver disease, and arthritis. The ultimate goal is to identify novel proteins and pathways relevant to these diseases, then translate this knowledge to develop novel therapeutics with improved efficacy. 

1) PCSK9-promoted LDLR degradation. Proprotein convertase subtilisin/kexin-type 9 (PCSK9) binds to LDLR, blocks recycling of LDLR to the cell surface, and then reroutes the receptor for lysosomal degradation. This reduces LDLR-mediated LDL uptake and increases circulating LDL cholesterol levels. Monoclonal antibody therapy to lower plasma LDL-C by inhibiting PCSK9 shows impressive LDL-C-lowering effect and reduced cardiovascular events. However, this costly treatment requires injections of large amounts of antibodies for clinical efficacy with extremely high production costs, placing a high burden on the health care system and limiting the therapy’s wide use as the treatment must be lifelong. Thus, there is an urgent need for an alternative strategy to inhibit PCSK9-promoted LDLR degradation, so that a more cost-effective alternative to antibody therapy can be developed. Currently, we are investigating:  A) The molecular mechanism by which PCSK9 promotes LDLR degradation. We have identified some cofactors that may play an essential roles in PCSK9-promoted LDLR degradation. We will determine the physiological roles of the identified proteins in lipid metabolism and in the development of atherosclerosis in vivo. B) Understanding PCSK9 secretion. Inhibition of PCSK9 secretion appears to be a promising therapeutic target. We found that a cargo receptor contributes to PCSK9 secretion. We will investigate how this protein facilitates PCSK9 secretion and determine its physiological role in lipid metabolism. Outcomes may pave the way for new therapies to lower LDL-C effectively and cost-efficiently.  We found that A) the C-terminal domain of PCSK9 and SEC24 isoforms are required for PCSK9 secretion (Biochim Biophys Acta–Molecular & Cell Biology of Lipids, 2020, 1865:158660). B) A cargo receptor (Surf4) was reported to facilitate secretion of PCSK9 that was overexpressed in HEK293 cells. However, we found that Surf4 is not required for endogenous PCSK9 secretion from human hepatocytes (Biochim Biophys Acta–Molecular & Cell Biology of Lipids, 2020, 1865: 158555) or mice (J Lipid Research, 2021, 62: 100091). C) The ligand binding repeats of LDLR play an important role in PCSK9 binding (J Lipid Research, 2019, 60: 516), suggesting a new therapeutic target for blocking the interaction between PCSK9 and LDL.

2) The role of membrane type-1 matrix metalloproteinase (MT1-MMP) in metabolism and human disease. Cell surface proteins can be cleaved by proteases, leading to the release of an extracellular domain (receptor shedding). The ectodomain of LDLR can be cleaved by proteases, and the released soluble ectodomain is detected in cell culture media and human plasma. The proteinase responsible for LDLR shedding, however, is unknown. We have made the following findings.

2A) We are the first to demonstrate that MMP14 promotes ectodomain cleavage of LDLR. Knockdown of MMP14 expression in mice increased LDLR levels in the liver, reduced plasma LDL cholesterol levels, and ameliorated the development of atherosclerosis in mice (Nat Commun; 2021). These findings indicate the potential of hepatic MMP14 as a therapeutic target for lowering plasma levels of LDL cholesterol. 

2B) We found that an amino acid residue in the MT-loop of MMP14 is critical for MMP14-promoted LDLR degradation (Frontier in Cardiovascular Medicine, 2022). MMP14 belongs to the matrix metalloproteinase (MMP) family, which has 23 members in humans. The catalytic domain of all MMPs is highly conserved, so designing catalytic domain-based inhibitors to target specific MMPs precisely is highly challenging. On the other hand, the MT-loop in MMP14 is specific for the metalloproteinase. Thus, our finding provides a basis for the design of a MMP14-specific inhibitor targeting its ability to cleave LDLR.

2C) We developed inducible global and chondrocyte-specific MT1-MMP knockout mice. We found that deficiency of global but not chondrocyte MMP14 causes overt arthritis in adult mice, indicating tissue/cell type-specific targeting of MMP14 is required for potential therapeutic treatment (Matrix Biology, 2023).

2D) We published two review articles discussing the most recent advances in the role of MMP14 in lipid metabolism, one in the Journal of Molecular Cell Biology/JMCB (2021) and one in Phytotherapy Research (2023). 

3) Understanding progressive familial intrahepatic cholestasis type 2 (PFIC-2). Bile salts are synthesized from cholesterol in the liver and then excreted to the bile through ATP-binding cassette transporter B11 (ABCB11).  Free cholesterol is directly pumped into the bile through the heterodimer ABCG5/G8. Mutations in ABCB11 cause PFIC-2, a rare autosomal recessive disorder that is characterized with hepatic accumulation of bile salts. PFIC-2 is an early-onset disorder, typically starting in infancy. Patients with PFIC-2 often suffer severe liver damage and develop liver failure or hepatocellular carcinoma early in their childhood.  Currently, PFIC-2 is  incurable. Treatment focuses on relieving clinical symptoms and slowing the progression of the disease. Ultimately, approximately half of PFIC-2 patients require liver transplantation before adulthood. Several lines of evidence show that PFIC-2 patients with specific missense mutations in ABCB11 respond well to certain treatments. Thus, tailored mutation-specific targeted pharmacological therapy is an efficient strategy to treating patients with PFIC-2. However, this requires clear genotype–phenotype correlation data that are not available.  Thus, we will investigate how mutations in ABCB11 impair its function.

4) Surf4 and lipid metabolism. Very low-density lipoprotein is primarily secreted from the liver and catabolized to LDL in the circulation. Reducing VLDL secretion can lower plasma LDL levels. However, current medicines targeting VLDL secretion, such as MTP inhibitor and apoB siRNA, cause severe side effects, such as fatty liver. We found that 

    4A) Surf4 mediates VLDL secretion in mice. Surf4 liver-specific knockout mice displayed a marked reduction in VLDL secretion and plasma triglyceride and cholesterol levels. We also found that knockdown of Surf4 significantly reduced the development of atherosclerosis in Ldlr-/- mice. Importantly, silencing hepatic Surf4 did not cause hepatic lipid accumulation or liver damage even though VLDL secretion was impaired, indicating that inhibiting hepatic Surf4 has the potential to treat hypercholesterolemia, especially for people with homozygous familial hypercholesterolemia (J Lipid Research, 2021). The paper was highlighted by the journal and featured by ASBMB Today from the American Society for Biochemistry and Molecular Biology, in which they stated that “The work contributes to researchers’ growing understanding of lipid metabolism regulation and how to minimize side effects of ASCVD treatment.”

4B) Lack of hepatic Surf4 significantly reduced cholesterol levels in the adrenal gland but did not impair the production of adrenal cortex hormones (Frontier in Cardiovascular Medicine, 2021).

4C) Knockdown of hepatic Surf4 significantly reduced VLDL secretion and plasma LDL cholesterol levels in apoE-/- mice, ameliorating atherosclerosis without causing hepatic lipid accumulation (Biochim Biophys Acta–Molecular & Cell Biology of Lipids, 2022;1867:159196).

4D) Conditional knockout of intestinal Surf4 significantly reduced intestinal lipid absorption, chylomicron secretion and plasma lipid levels (Arterioscler Thromb Vasc Biol., 2023, 43(4):562-580). Figures of this paper were selected by the Journal Editor for ATVB April 2023 cover image.

4E) We published a review article to discuss the most recent advances in the role of Surf4 in cargo secretion and lipid metabolism (Journal of Molecular Cell Biology,  2022, 14 (9): mjac063).