Discovery could pave way for development of therapies to treat non-alcoholic steatohepatitis

UT Southwestern immunologists have discovered a key pathogenic event caused by obesity that can trigger severe forms of non-alcoholic fatty liver disease and eventual liver failure. The discovery, published in Immunitymight pave the way for the development of therapies to treat non-alcoholic steatohepatitis (NASH).

The team led by Zhenyu Zhong, Ph.D., and Shuang Liang, Ph.D., assistant professors of immunology, revealed that persistent obesity can damage a macrophage receptor, called TREM2, thereby disabling a critical function which otherwise keeps liver inflammation in check. The imbalance then fuels the chronic inflammation of the liver to allow the development of NASH.

NASH is an aggressive form of non-alcoholic fatty liver disease (NAFLD) – a range of chronic liver disorders that begin as mild fatty liver disease but can progress to more advanced stages of the disease, including NASH, cirrhosis and even carcinoma hepatocellular (HCC), the dominant form of primary liver cancer. The underlying molecular mechanisms that cause fatty liver disease to evolve into NASH and beyond have eluded researchers, creating significant hurdles to the development of effective therapies.

Filling this knowledge gap, Drs. Zhong and Liang found that dietary obesity upregulates TREM2 expression in liver-infiltrating macrophages – a critical population of immune cells responsible for clearing lipid-damaged hepatocytes. “The clearance of these damaged cells by macrophages (a process also called efferocytosis) is essential for maintaining liver immune silencing in fatty liver to prevent chronic inflammation and NASH,” Dr. Liang said.

When examining TREM2 expression during NASH development, researchers unexpectedly found that persistent obesity significantly impairs the macrophage-dependent clearance of lipid-damaged hepatocytes by inducing the cleavage and inactivation of TREM2.

We discovered that two pro-inflammatory cytokines, TNF and IL-1β, activate a proteinase named ADAM17 in macrophages which in turn cleaves and inactivates TREM2. This leads to an aberrant accumulation of dying, lipid-laden hepatocytes in the liver, where they cause chronic liver inflammation and the subsequent development of NASH. We believe that blocking TREM2 cleavage to restore the macrophage’s ability to clear lipid-damaged hepatocytes has great potential to treat NASH.

Dr Zhenyu Zhong, Ph.D., membre du Harold C. Simmons Comprehensive Cancer Center et Cancer Prevention and Research Institute of Texas Scholar in Cancer Research at UT Southwestern

Additionally, they found that the cleaved product, soluble TREM2 (sTREM2), which is dramatically elevated in the circulation of mice and patients with NASH, can serve as a non-invasive biomarker for NASH.

The Zhong Lab focuses on understanding the fundamental molecular mechanisms by which chronic liver inflammation is established. “With the unprecedented obesity epidemic, NASH has become a major chronic liver disorder, affecting approximately 3-5% of the world’s population,” said Dr. Zhong, member of the Graduate School’s Division of Basic Sciences. of Biomedical Sciences from UT Southwestern. . “By deploying a combination of biochemical, genetic, molecular, immunological, imaging and histochemical tools as well as single-cell ‘omics’ analyses, our ultimate goal is to reveal the fundamental molecular mechanisms underlying chronic inflammation of the liver and to explore whether new mechanistic mechanisms this knowledge might be applied to promote liver repair and regeneration following injury, thereby preventing progression from NAFLD to NASH and HCC. »

Other UTSW researchers who contributed to the study are Xiaochen Wang, Chuanli Zhou, Danhui Liu, Naoto Fujiwara, Naoto Kubota, Arielle Click, Polly Henderson, Janiece Vancil, Cesia Ammi Marquez, and Yujin Hoshida.

This study was supported by grants from the American Association for the Study of Liver Diseases, the Texas Institute for Cancer Prevention and Research, and the National Institutes of Health. Additional support included computational support from the Lyda Hill Department of Bioinformatics BioHPC supercomputing facility at UT Southwestern, the UTSW Flow Cytometry Core facility, and the UTSW Circle of Friends in Cancer Research award, among others.