580 California St., Suite 400
San Francisco, CA, 94104
Key research themes
1. How is cholesterol 7α-hydroxylase regulated in hepatic cholesterol and bile acid metabolism?
This research area investigates the regulation of cholesterol 7α-hydroxylase, the rate-limiting enzyme in cholesterol catabolism to bile acids in the liver, and explores how bile acid flux, substrate availability, and feedback mechanisms modulate its activity, enzyme mass, and gene expression. Understanding these regulatory layers is pivotal to the control of cholesterol homeostasis and bile acid synthesis, impacting lipid metabolism and related diseases.
Key finding: Using bile fistula rat models with controlled infusion of taurocholate (7α-hydroxylated bile acid) and mevalonolactone (cholesterol precursor), this study demonstrated that interruption of enterohepatic circulation... Read more
Key finding: This study revealed spatial heterogeneity of cholesterol 7α-hydroxylase expression within the rat liver lobule, with predominant pericentral hepatocyte localization evidenced by enzyme activity, mRNA, and transcriptional... Read more
Key finding: This investigation demonstrated that feeding rats with high dietary cholesterol markedly decreases hepatic HMG-CoA reductase enzyme activity without significantly altering its mRNA levels, indicating post-transcriptional... Read more
Key finding: Through systematic testing of 27 bile acids with varied hydroxylation patterns on cultured rat hepatocytes, this study found that bile acid-mediated suppression of cholesterol 7α-hydroxylase and sterol 27-hydroxylase occurs... Read more
Key finding: This study employed 25-hydroxycholesterol cytotoxicity selection to generate a rat hepatoma cell line (L35) expressing endogenous cholesterol 7α-hydroxylase activity and mRNA, conferring resistance. The expressed enzyme was... Read more
2. What roles do de novo cholesterol synthesis pathways and their enzymes play in cancer progression and therapy?
This theme focuses on the contribution of cholesterol biosynthesis, particularly the mevalonate pathway and its enzymes such as HMG-CoA reductase (HMGCR), DHCR24, and DHCR7, to tumorigenesis, cancer proliferation, metastasis, and survival. Research explores functional enzyme interactions, transcriptional regulation, and potential therapeutic targeting of cholesterol synthetic enzymes in various malignancies, reflecting the importance of metabolic reprogramming in oncology.
Key finding: This review synthesizes evidence indicating upregulation of cholesterol synthesis enzymes, including HMG-CoA reductase (HMGCR), squalene epoxidase, and downstream sterol reductases, supports tumor progression and metastasis... Read more
Key finding: Using co-immunoprecipitation and functional assays in mammalian cells, this study revealed a novel physical and functional interaction between DHCR24 and DHCR7, the two terminal reductases in the cholesterol biosynthesis... Read more
Key finding: Employing a liver-specific Fasn (fatty acid synthase) knockout mouse model of hepatocellular carcinoma (HCC), the study demonstrated that while Fasn ablation delays tumorigenesis, eventual HCC emergence occurs through... Read more
3. How does modulation of cholesterol synthesis and metabolism affect insulin secretion and lipid homeostasis?
This theme addresses mechanistic investigations into the roles of cholesterol and its biosynthetic intermediates in pancreatic β-cell function, particularly insulin secretion, and systemic lipid metabolism. It includes evaluation of enzyme inhibition effects, substrate supply, and membrane cholesterol dynamics, important for understanding diabetes pathophysiology and metabolic regulation.
Key finding: The study dissected the roles of isoprenoid intermediates and cholesterol in glucose-stimulated insulin secretion (GSIS) using pharmacologic inhibitors in INS-1E cells and mouse islets. Acute hydroxymethylglutaryl-CoA... Read more
Key finding: This research showed that inhibition of Acyl-CoA:cholesterol acyltransferase (ACAT) by avasimibe decreases intracellular cholesteryl ester storage in rat hepatocytes and increases bile acid synthesis and cholesterol... Read more
Key finding: Using in vivo kinetic techniques, this study quantified hepatic and intestinal cholesterol synthesis rates in lysosomal acid lipase-deficient mice, a model of cholesterol ester storage disease, and evaluated effects of... Read more