Research

Research Background

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an umbrella term encompassing a spectrum of conditions, including fatty liver, steatohepatitis (MASH), cirrhosis, and hepatocellular carcinoma. It represents the hepatic manifestation of metabolic syndrome, which includes conditions such as obesity, diabetes, and cardiovascular diseases.

Fatty liver refers to an excessive accumulation of fat in the liver, a condition observed in approximately 30% of the adult population. Fatty liver does not typically result in significant liver dysfunction; however, approximately 20% of cases progress to MASH, a pathological condition characterized not only by fat accumulation but also by liver injury, inflammation, and fibrosis. 

As MASH advances to irreversible stages, such as cirrhosis and hepatocellular carcinoma, it is essential to understand the mechanisms underlying the progression of fatty liver to MASH and to develop targeted therapeutics that can prevent this progression.

We have focused on elucidating the molecular mechanisms underlying steatotic liver diseases, encompassing hepatic fat accumulation, tissue damage, inflammation, and fibrosis. The goal of this research is to identify novel therapeutic targets for MASLD and other metabolic syndromes.

As part of this effort, we have examined the role of neutrophils in the progression of fatty liver to MASH. CXCL1 and IL-8 are key chemokines that induce neutrophil chemotaxis. By overexpressing CXCL1 and/or IL-8 in the liver of obese mice, we have highlighted the critical role of hepatic neutrophils the progression of MASLD.  Furthermore, we have elucidated the disruption of intracellular signaling pathways in hepatocytes resulting from interactions with infiltrating neutrophils during MASLD progression.

Ongoing Studies

[1] The role of chemokines in the development of liver diseases

• Studies utilizing genetically modified mice with alterations in the chemokine genes aim to elucidate the mechanisms by which chemokines regulate immune cell recruitment and subsequent liver pathology. 

[2] The contribution of inter-organ crosstalk in the development of liver diseases

• Genetic Modifications in Animals: Utilizing genetically modified mouse models with targeted alterations in genes regulating liver-adipose tissue communication to identify pathways contributing to liver pathophysiology.

• Gut Microbiome-Derived Compounds: Exploring the impact of microbiota-derived metabolites on liver physiology and pathology, including their role in modulating lipid metabolism, inflammation, and fibrosis.

[3] Pharmacological intervention studies of liver diseases 

• MASLD-Ameliorating Small Molecule Compounds: Investigating the therapeutic potential of small molecule compounds in mitigating MASLD. These studies aim to elucidate their efficacy and mechanisms of action in cultured cells and animal models.