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 LDL receptors (LDLR), preventing their recycling to the cell surface and redirecting them to lysosomal degradation. This process reduces LDLR-mediated LDL uptake, leading to elevated circulating LDL cholesterol (LDL-C) levels. Monoclonal antibody and siRNA therapies targeting PCSK9 have demonstrated significant LDL-C-lowering effects and reduced cardiovascular events. However, these treatments are costly, which places a substantial burden on healthcare systems and limits accessibility, especially given the necessity for lifelong treatment. Consequently, there is an urgent need for alternative, cost-effective strategies to inhibit PCSK9-mediated LDLR degradation.

Our current research focuses on two key areas:

1. Molecular Mechanisms of PCSK9-Mediated LDLR Degradation
   We have identified potential cofactors involved in PCSK9-promoted LDLR degradation. Ongoing studies aim to elucidate their physiological roles in lipid metabolism and atherosclerosis development in vivo.

2. PCSK9 Secretion Pathways
   Targeting PCSK9 secretion presents a promising therapeutic approach. Our findings indicate that a specific cargo receptor contributes to PCSK9 secretion. We are investigating how this protein facilitates PCSK9 secretion and its role in lipid metabolism.

These studies aim to pave the way for novel, cost-effective therapies to lower LDL-C.

Key findings from our work include:

1A) 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).

1B) Surf4 is not required for endogenous PCSK9 secretion in human hepatocytes (Biochim Biophys Acta–Molecular & Cell Biology of Lipids, 2020, 1865:158555) or in mice (J Lipid Research, 2021, 62:100091).

1C) The ligand-binding repeats of LDLR play a critical role in PCSK9 binding (J Lipid Research, 2019, 60:516), suggesting a potential therapeutic target for disrupting the PCSK9-LDLR interaction.

These insights provide a foundation for developing alternative strategies to inhibit PCSK9 activity, offering a more sustainable and accessible approach to managing LDL-C levels and reducing cardiovascular risk.

2) The role of membrane type-1 matrix metalloproteinase (MT1-MMP) in metabolism and human disease. Cell surface proteins can be cleaved by proteases, resulting in the release of an extracellular domain—a process known as receptor shedding. For example, the ectodomain of the LDL receptor (LDLR) is cleaved by proteases, with the resulting soluble ectodomain detectable in cell culture media and human plasma. However, the protease responsible for LDLR shedding has remained unidentified. Our research has made the following key discoveries:

2A) We were the first to demonstrate that MMP14 promotes ectodomain cleavage of LDLR. In mice, knockdown of Mmp14 expression increased hepatic LDLR levels, reduced plasma LDL cholesterol, and ameliorated atherosclerosis development (Nat Commun, 2021). These findings suggest that hepatic MMP14 could serve as a therapeutic target for lowering plasma LDL cholesterol levels. 

2B) We identified an amino acid residue in the MT-loop of MMP14 as critical for its role in promoting LDLR degradation (Frontiers in Cardiovascular Medicine, 2022). MMP14 belongs to the matrix metalloproteinase (MMP) family, which comprises 23 members in humans, all with highly conserved catalytic domains. This conservation makes it challenging to design inhibitors specific to a single MMP based on the catalytic domain. However, the MT-loop is unique to MMP14, providing a promising basis for developing a specific inhibitor that targets its LDLR-cleaving activity.

2C) Using inducible global and chondrocyte-specific MMP14 knockout mice, we discovered that global, but not chondrocyte-specific, deficiency of MMP14 causes overt arthritis in adult mice. This finding highlights the importance of tissue- or cell-type-specific targeting of MMP14 for potential therapeutic applications (Matrix Biology, 2023).

2D) We have published two comprehensive reviews on recent advances in understanding the role of MMP14 in lipid metabolism: one in the Journal of Molecular Cell Biology (JMCB, 2021) and another in Phytotherapy Research (2023).

3) Understanding progressive familial intrahepatic cholestasis type 2 (PFIC-2). 

Bile salts are synthesized from cholesterol in the liver and excreted into bile via the ATP-binding cassette transporter B11 (ABCB11). Free cholesterol, on the other hand, is directly transported into bile by the heterodimer ABCG5/G8. Mutations in ABCB11 result in progressive familial intrahepatic cholestasis type 2 (PFIC-2), a rare autosomal recessive disorder characterized by hepatic accumulation of bile salts. PFIC-2 typically manifests in infancy and is associated with severe liver damage, often progressing to liver failure or hepatocellular carcinoma during early childhood.

Currently, there is no cure for PFIC-2. Management focuses on alleviating clinical symptoms and slowing disease progression, but approximately half of the patients require liver transplantation before reaching adulthood. Emerging evidence suggests that some PFIC-2 patients with specific ABCB11 missense mutations respond favorably to targeted pharmacological treatments. This highlights the potential of mutation-specific therapies as an effective strategy for managing PFIC-2. However, the development of such therapies is hindered by the lack of comprehensive genotype-phenotype correlation data.

To address this gap, our study aims to investigate how ABCB11 mutations impair its function. This research is critical for advancing personalized therapeutic approaches for PFIC-2 patients.

4) Surf4 and lipid metabolism. 

Very low-density lipoprotein (VLDL) is primarily secreted by the liver and metabolized into low-density lipoprotein (LDL) in circulation. Reducing VLDL secretion can effectively lower plasma LDL levels. However, current therapies targeting VLDL secretion, such as microsomal triglyceride transfer protein (MTP) inhibitors and apoB siRNA, often result in severe side effects, including fatty liver disease.

Key Findings on Surf4 in Lipid Metabolism:

1. Surf4 Mediates VLDL Secretion in Mice
   Liver-specific knockout of Surf4 significantly reduced VLDL secretion, resulting in lower plasma triglyceride and cholesterol levels in mice. Additionally, knockdown of Surf4 reduced atherosclerosis development in Ldlr-/- mice. Importantly, silencing hepatic Surf4 did not cause hepatic lipid accumulation or liver damage, suggesting its therapeutic potential for treating hypercholesterolemia, particularly in individuals with homozygous familial hypercholesterolemia (J Lipid Research, 2021). This study was highlighted by the journal and featured in ASBMB Today, which noted that the findings contribute to understanding lipid metabolism regulation while minimizing ASCVD treatment side effects.

2. Impact on Adrenal Cholesterol and Hormones
   Hepatic Surf4 deficiency significantly reduced adrenal gland cholesterol levels without impairing adrenal cortex hormone production (Frontiers in Cardiovascular Medicine, 2021).

3. Reduction of Atherosclerosis in ApoE-/- Mice
   Knockdown of hepatic Surf4 decreased VLDL secretion and plasma LDL cholesterol levels in apoE-/- mice. This intervention ameliorated atherosclerosis without inducing hepatic lipid accumulation (Biochim Biophys Acta – Molecular & Cell Biology of Lipids, 2022; 1867:159196).

4. Role of Intestinal Surf4 in Lipid Absorption
   Conditional knockout of intestinal Surf4 markedly reduced intestinal lipid absorption, chylomicron secretion, and plasma lipid levels. Figures from this study were featured as the cover image of Arteriosclerosis, Thrombosis, and Vascular Biology in April 2023 (ATVB, 2023; 43(4):562-580).

5. Review of Surf4 in Lipid Metabolism
   A review article discussing recent advances in the role of Surf4 in cargo secretion and lipid metabolism was published in Journal of Molecular Cell Biology (J Mol Cell Biol, 2022; 14(9): mjac063).

6. Role of Hepatic Surf4 in liver fibrosis.

Surf4 mediates serum amyloid A1 (SAA1) secretion and promotes liver fibrosis. Hepatic Surf4 deficiency markedly reduces SAA1 secretion from hepatocytes and ameliorates liver fibrosis in mice (Research, 2024, Aug 5;7:0435. doi: 10.34133/research.0435).

7. Effects of Surf4 whole body knockout.

The inducible global knockout of Surf4 in adult mice leads to significant metabolic and physiological disturbances, including hypolipidemia, intestinal lipid accumulation, liver injury, and increased mortality (Biochim Biophys Acta Mol Cell Biol Lipids. 2024 Nov 15;1870(2):159577. doi: 10.1016/j.bbalip.2024.159577)