DALLAS – December 23, 2022 – Immunologists at UT Southwestern University Discover Key Pathogenic Events Caused by Obesity That Can Lead to Severe Nonalcoholic Fatty Liver Disease and Chance of Liver Failure Did.Findings published in immunitymay pave the way for developing therapies to treat non-alcoholic steatohepatitis (NASH).
Zhenyu Zhong, Ph.D.
the team led by Zhenyu Zhong, Ph.D.When Dr. Shuang Liang,Assistant professor immunologyrevealed that persistent obesity can damage a macrophage receptor called TREM2, thereby abrogating its key function in reducing inflammation in the liver. It promotes chronic liver inflammation and allows the development of NASH.
NASH is an aggressive form of nonalcoholic fatty liver disease (NAFLD). It is a continuum of chronic liver damage that begins as benign fatty liver and can progress to more advanced disease stages such as NASH, cirrhosis, and even hepatocellular carcinoma (HCC). of primary liver cancer. The molecular mechanisms underlying the progression of fatty liver disease to his NASH and beyond have kept researchers elusive and have been a major obstacle to developing effective treatments.
Fill this knowledge gap, Dr. Zhong and Liang found that dietary obesity upregulated TREM2 expression in liver-infiltrating macrophages, a key population of immune cells involved in the elimination of lipid-damaged hepatocytes. “Clearance of these damaged cells by macrophages, a process also called efferocytosis, is key to maintaining hepatic immune silencing in fatty liver to prevent chronic inflammation and NASH,” Dr. Liang said.
Dr. Shuang Liang
Examining TREM2 expression during NASH development, the researchers unexpectedly found that persistent obesity induces TREM2 cleavage and inactivation, leading to macrophage-dependent changes in lipid-damaged hepatocytes. I have found that it severely impairs removal.
“We found that two pro-inflammatory cytokines, TNF and IL-1β, activated a proteinase named ADAM17 in macrophages that cleaved and inactivated TREM2. Abnormal accumulation of hepatocytes in the liver leads to chronic liver inflammation and subsequent development of NASH. Harold C. Simmons Comprehensive Cancer Center Texas Scholar Cancer Prevention and Institute in Cancer Research at UT Southwestern. “We believe that blocking TREM2 cleavage and restoring the ability of macrophages to clear lipid-damaged hepatocytes has great potential for treating NASH.”
Furthermore, they found that the cleaved product, soluble TREM2 (sTREM2), was greatly elevated in its abundance in the circulation of mice and patients with NASH and serves as a noninvasive biomarker of NASH. did.
Naka Laboratory It focuses on understanding the underlying molecular mechanisms by which chronic hepatitis is established. “With the unprecedented obesity epidemic, NASH has become a major chronic liver disorder, affecting about 3% to 5% of the world’s population,” said a member of UT Southwestern’s Department of Basic Sciences. Dr. Zhong said. Graduate School of Medicine, Dentistry and Pharmaceutical Sciences“By deploying biochemical, genetic, molecular, immunological, imaging, and histochemical tools combined with single-cell ‘omics’ analysis, our ultimate goal is to: To clarify the basic molecular mechanisms underlying chronic hepatitis and to investigate whether there are such new mechanisms. This insight may aid in liver repair and regeneration after injury, thereby preventing the progression of NAFLD to NASH and HCC. “
Other UTSW researchers who contributed to this study are Xiaochen Wang, Chuanli Zhou, Danhui Liu, Naoto Fujiwara, Naoto Kubota, Arielle Click, Polly Henderson, Janiece Vancil, Cesia Ammi Marquez, and Hiroto Hoshida.
This research American Liver Society, Texas Cancer Prevention Institute, and the National Institutes of Health. Additional support included computational support from the BioHPC supercomputing facility. Lyda Hill Bioinformatics Division At UT Southwestern, UTSW Flow Cytometry Core Facilityand the UTSW Circle of Friends Award in Cancer Research.
About UT Southwestern Medical Center
One of the nation’s leading academic medical centers, UT Southwestern combines pioneering biomedical research with excellence in clinical care and education. The institution’s faculty has won his six Nobel Prizes, his 24 members of the National Academy of Sciences, his 18 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute research person is included. More than 2,900 full-time faculty members are responsible for groundbreaking medical advances and are committed to rapidly translating science-driven research into new clinical treatments. A UT Southwestern physician, in more than 80 specialties, he provides care to over 100,000 inpatients, over 360,000 emergency room cases, and supervises nearly 4 million outpatient visits annually. .
