The overall theme of our research is the regulation of energy homeostasis, lipid metabolism, lipid peroxidation, inflammation and cell death in mammalian systems, with special emphasis on adipose tissue, liver, immune system, and blood vessels. We work at biochemical and physiological levels, employing clinical knowledge, genetically engineered animal models, surgically, dietarily or chemically-induced disease models, and multi-omics approaches to identify new therapeutic targets for human diseases including diabetes, fatty liver diseases, liver cancer, and cardiovascular diseases.
CURRENT RESEARCH AREA
Atherosclerosis and lipid metabolism
Atherosclerosis and its complications, like heart attack and stroke, are the leading causes of death in modern society. Atherogenesis results from hypercholesterolemia, systemic chronic inflammation, and aortic cell dysfunctions. We are interested in understanding the regulation of cholesterol metabolism, inflammation and vascular functions under physiological and pathological conditions. Our recent work discovered the roles of oxidative stress and oxidized LDL (OxLDL) in atherosclerosis, a chronic, progressive disease that eventually leads to ischemic heart attack and stroke. Elevated levels of LDL cholesterol (the “bad” cholesterol) significantly raise the risk of atherosclerosis. Infiltration and retention of LDL in the artery wall, especially in regions of disturbed flows in vascular niches such as branches and curves, followed by their oxidation (OxLDL) under conditions of oxidative stress, is held to be a key-initiating event that causes early atherogenesis. OxLDL contains several bioactive lipid peroxidation products (LPPs), including oxidized phospholipids (OxPLs), malondialdehyde (MDA), and 4-hydroxynonenal (4-HNE). Together with the local atherogenic disturbed flow, LPPs induce vascular dysfunction and inflammation to promote atherogenesis. We are currently taking in vitro and in vivo approaches, including our unique transgenic mouse models that express natural antibodies (Abs) specifically target LPPs to explore modes of LPPs regulation during atherogenesis. We hope to understand how LPPs contribute to atherosclerosis at the systemic, cellular, and molecular levels.
NAFLD has become a major cause of end-stage liver diseases including cirrhosis and HCC. Besides liver-related complications, patients with NAFLD have higher-than-usual risk for cardiovascular disease (CVD). NAFLD is an umbrella term that comprises simple fatty liver (NAFL) that could be reversed by lifestyle management, and nonalcoholic steatohepatitis (NASH), a progressive form of NAFLD that need medical intervention. However, as a critical stage of liver disease that could transform into cirrhosis and HCC, there is still no FDA-approved medication to treat NASH. Our lab is interested in understanding the causes of the heterogeneous pathology of NASH, including hepatic steatosis, inflammation, liver injury, and fibrosis with the goal of identifying novel targets to reverse NASH and prevent its progression to HCC. Our recent work discovered the pathogenic roles of OxPLs in the progression of NASH and HCC. It unravels LPPs as novel therapeutic targets in NASH and HCC. The fundamental regulation of LPPs in cellular and subcellular functions including lipid metabolism, mitochondria function, oxidative stress, inflammation, and fibrosis has become an area with tremendous opportunity for advancement in metabolic and cancer research.
Nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC)
Hepatocellular death, characterized by swollen hepatocytes on liver biopsy, has an essential role in the progression of NAFLD. In healthy liver, hepatocyte apoptosis has a key role in liver homeostasis, maintaining equilibrium between hepatocyte loss and replacement. However, pathological conditions such as viral infection, alcoholic or nonalcoholic steatohepatitis, and physical injury lead to extensive hepatocyte death and liver damage. We are interested in understanding the molecular mechanisms that control hepatocellular death to improve liver injury and prevent fibrosis thereby to more effectively treat NASH. Our recent study uncovered a striking role of the energy metabolism in the control of hepatocellular death in NASH. By using a combination of technologies including in-depth biochemical and structural analysis, Adeno-associated virus (AAV)-mediated gene delivery, proteomics, and high-throughput drug screening, we hope to elucidate the cellular and molecular events that control hepatocellular death and understand how the balance between homeostatic cell turnover and sustained cell death is controlled. Altogether we hope to find ways to prevent or reverse liver damage, fibrosis, and organ failure to treat NASH and prevent end-stage liver diseases.
Obesity and Diabetes
Obesity has become a worldwide pandemic. It is a major risk factor for numerous diseases, particularly insulin resistance and type 2 diabetes. Overnutrition and/or aging disrupts metabolic homeostasis. Positive energy balance caused by excess energy intake or insufficient energy expenditure results in fat accumulation. Abnormal lipid accumulation could lead to the alteration of basal and insulin-regulated glucose metabolism. Our lab investigates the regulation of energy metabolism, glucose metabolism, and lipid metabolism to identify new therapeutic targets and strategies to treat diabetes. We are particularly interested in the biochemical events in these disorders that shift energy balance and induce inflammation in vivo. We recently found that the noncanonical IKK family member TANK-binding kinase 1 (TBK1) uniquely controls bidirectional crosstalk between energy sensing and inflammatory through the regulation of a complex signaling network that involves AMPK, Unc-51-like autophagy-activating kinase 1 (ULK1), NF-κB inducing kinase (NIK), and NF-κB in both over- and undernutrition in obesity and diabetes. Our ongoing studies employ high throughput transcriptomic and proteomic screening to identify novel pathogenic factors in obesity and utilizes a drug screening approach to precisely target the identified pathogenic factors for diabetes treatment.
The Zhao / Sun lab integrates state-of-the-art multi-omics approaches with human and genetically engineered mouse systems to understand chronic metabolic diseases. We employ genetic, nutritional, surgical and other environmental manipulations in mouse models to mimic human metabolic disease and target identified pathogenic players to treat diseases. This translational approach has had a great impact on our understanding of disease pathophysiology, enabling us to identify new disease targets and conduct intervention studies to more effectively prevent or treat diseases.