Hong Lu, PhD
CLINICAL BACKGROUND AND MY APPROACH TO CARE
Mechanism(s) and biomarker(s) of non-responsiveness to glucocorticoid therapy in patients with severe alcoholic hepatitis
RESEARCH PROGRAMS AND AFFILIATIONS
- Nuclear receptors in regulation of hepatic gene expression and liver diseases
- Progression of alcoholic/non-alcoholic fatty liver to steatohepatitis, liver cirrhosis, and liver cancer
- Development of liver-targeting prodrugs and liver-specific delivery of genes/proteins
- Hepatokines in regulation of immune function and liver regeneration
As the metabolic center, liver is vital for the survival of the organism due to its critical role in nutrition and detoxification of xenobiotics and metabolic wastes. Alcoholic liver disease (ALD) is a major cause of death worldwide. Alcoholic hepatitis is a severe form of ALD with high mortality that features jaundice, steatohepatitis, and cholestatic liver injury. Additionally, in modern society, a pandemic of overeating high-fat-high-sugar-diet, obesity, and diabetes drives non-alcoholic fatty liver disease (NAFLD), the most common liver disease in the US. NAFLD is closely associated with hyperlipidemia, a major risk factor of cardiovascular diseases. Moreover, NAFLD can progress to more malignant liver diseases, such as non-alcoholic steatohepatitis (NASH), liver cirrhosis, and liver cancer. Nuclear receptors are master regulators of gene expression and key drug targets. The major research interest of my laboratory is to understand how nuclear receptors regulate ALD and NAFLD and the progression of fatty liver to steatohepatitis, liver cirrhosis, and liver cancer, in order to develop novel preventive and therapeutic approaches for these liver diseases.
Interaction of genetic susceptibility with environmental exposure determines the final penetrance of metabolic diseases. Hepatic expression of hepatocyte nuclear factor 4α (HNF4α), a master regulator of basal liver functions, is highly variable among normal populations and markedly decreased in diabetes, ALD, NAFLD/NASH, liver cirrhosis, and liver cancer. HNF4α crosstalks with diverse signaling pathways to regulate liver metabolism. Circulating glucocorticoids, acting via the key stress regulator glucocorticoid receptor (GR), are altered during various psychological, metabolic, and inflammatory stresses. We found that crosstalk of the master regulator HNF4α with the stress regulator GR plays a key role in regulating liver metabolism and the progression of ALD and NAFLD. We are using functional genomics approach of inducible liver-specific knockout and knockin mice, RNA-sequencing, ChIP-sequencing, metabolomics, and luciferase reporter assays to understand how the HNF4α-GR crosstalk regulates hepatic gene expression, inflammation, and metabolic function in ALD, NAFLD, and liver cancer.
Due to their essential roles in anti-inflammation and liver protection, glucocorticoids (GCs) account for almost one third of the global drug market for liver diseases; however, GCs' many side effects on extrahepatic tissues is the limiting factor for using GCs to treat diverse liver diseases and sepsis in patients. Chronically elevated circulating GCs in extrahepatic tissues promote overeating (in brain), insulin resistance and fatty liver (in muscle), and abdominal fat stores. GCs are currently the only drugs for severe alcoholic hepatitis, with limited efficacy. How to enhance/maintain the beneficial effects and avoid the side effects of GCs remains challenging. Liver-specific delivery of GCs will markedly improve the current GC therapy of liver diseases. By collaborating with Dr. Juntao Luo, a medicinal chemist in our department, we have developed novel liver-targeting GC prodrugs for the treatment of ALD and NAFLD. Additionally, estrogens have many beneficial effects on the liver via increasing insulin sensitivity, lipid metabolism, and liver regeneration. Importantly, decreases of hepatic estrogen receptor (ERα) correlate with the severity of ALD in humans. We found that GCs crosstalk with estrogens in human hepatocytes, resulting in a highly desirable hepatoprotective gene expression profile. We have developed mice with inducible liver-specific double knockout of GR-ERα for basic research and liver-targeting estrogen prodrugs to further improve the GC therapy of liver diseases.
Non-responsiveness to GC (GC-NR) therapy is a major challenge in the clinics. Literature suggest that decrease of hepatic GR proteins is an important mechanism of GC-NR in severe alcoholic hepatitis; however, other mechanism(s) of GC-NR also exist. We have identified a novel non-phosphorable modification of GR with enhanced biological activities. Liver-specific mRNA delivery mediated by lipid nanoparticles (LNP) is a very promising therapeutic approach for liver diseases. Our department recently recruited a new faculty, Dr. Yamin Li, a medicinal chemist with extensive expertise at LNP-based gene/protein delivery, particularly liver-specific mRNA delivery. We will collaborate with Dr. Li to develop innovative LNP-based approaches of liver-specific mRNA delivery/co-delivery of wildtype and fortified GR, HNF4α, and ERα, as novel therapeutics for ALD, NAFLD, and liver cancer. Additionally, we are collaborating with hepatologists at Upstate hospital to initiate a clinical study to determine the mechanism(s) and biomarker(s) of GC-NR in patients with severe alcoholic hepatitis. Ultimately, results from these drug developments and clinical studies will help achieve optimized therapy of liver diseases.
Link to Pubmed