(Press-News.org) Formerly known as nonalcoholic steatohepatitis, metabolic dysfunction-associated steatohepatitis (MASH) is an inflammatory disease characterized by liver scarring or fibrosis that progressively impairs liver function.
It is a major risk factor for cirrhosis and liver cancer. And because treatment options are limited, MASH is the second leading cause for liver transplants in the United States after cirrhosis caused by chronic hepatitis C infection.
A better understanding of the pathological processes that drive MASH is critical to creating effective treatments. In a new paper published August 19, 2024 in PNAS, a team of scientists from Sanford Burnham Prebys, the University of California San Diego School of Medicine and elsewhere, describe the complex interplay between diseased liver cells and macrophages — a type of white blood cell whose jobs include killing and removing harmful cells and pathogens and helping to spur normal healing.
Debanjan Dhar, PhD, associate professor in the Cancer Genome and Epigenetics Program at Sanford Burnham Prebys, is senior author of the study. David Brenner, MD, president and CEO of Sanford Burnham Prebys, and Christopher Glass, MD, PhD, professor of cellular and molecular medicine at UC San Diego, are corresponding authors. Souradipta Ganguly, PhD, a postdoctoral research fellow at UC San Diego and Sanford Burnham Prebys, is first author.
The researchers found that the heterogeneous mix of macrophages involved with MASH was different, depending on whether the disease was progressing or regressing. More importantly, they identified specific macrophage subpopulations that are critical for resolving MASH and liver fibrosis in which accumulating scar tissue impairs the organ’s ability to function or repair itself. These fibrotic bands restrict blood flow, imperiling the entire organ.
“In MASH, Kupffer cells (a type of macrophage that resides in the liver) are lost and replaced by four distinct macrophage subpopulations. When the disease is in regression — that is, symptoms or severity are decreasing — two lipid associated macrophage subpopulations are dominant and express TREM2, a cell receptor that regulates cell survival, proliferation and anti-inflammatory responses,” said Brenner.
“MASH regression occurs in the presence if TREM2+ macrophages. They not only restrict the progression of MASH-fibrosis, but effectively slow it and reduce inflammation. The absence of TREM2+ macrophages allows the disease to progress.”
In early and moderate stages, MASH often produces no tell-tale symptoms, which is part of the why it has reached epidemic proportions in the U.S. The American Liver Foundation estimates 80 to 100 million Americans have fatty liver disease which, undiagnosed and untreated, progresses to nonalcoholic steatohepatitis, MASH, cirrhosis, liver cancer and death, often in combination with other conditions, such as obesity.
An estimated 1.5% to 6.5% of U.S. adults have MASH. afflicted by the condition, and roughly 24% of adults have metabolic dysfunction-associated steatotic fatty liver disease, the starting point for MASH, cirrhosis and worse.
“Our findings suggest that lipid associated macrophages that express TREM2 and TREM2 are required both for the emergence of more liquid associated macrophages and for their reparative functions,” said Dhar.
“Effective degradation of scar tissue as a protective mechanism is mediated by TREM2, and the absence of TREM2+ macrophages not only disrupts the liver’s ability to remove fibrotic tissue, but it also harms the entire immune response and healing process.”
Going forward, the scientists say a TREM2 agonist — a drug or substance that mimics the function of TREM2 — might be beneficial for MASH/fibrosis therapy and help spur MASH and fibrosis regression in patients also undergoing lifestyle modification, weight loss or bariatric surgery.
“There is only one approved treatment for MASH, and it was only approved earlier this year,” said Glass. “Any opportunities to expand clinical options that benefit patients need to be thoroughly pursued because liver disease in this country — and around the world — is only getting worse.”
Additional authors on the study include Sara Brin Rosenthal, Kei Ishizuka, Theresa V. Rohm, Naser Khader, Sebastiano Archilei, Jerrold M. Olefsky, Ariel E. Feldstein, Tatiana Kisseleva and Rohit Loomba, all at UC San Diego; Ty D. Troutman, UC San Diego and Cincinnati Children’s Hospital Medical Center, and German Aleman Muench, Yasuyo Sano and Pejman Soroosh, Janssen Research & Development, San Diego.
This study was supported by National Institutes of Health grants to D.D. (R01DK137061, R01DK133930), Altman Clinical and Translational Research Institute (ACTRI – KL2TR001444) and the San Diego Digestive Diseases Research Center (NIH DK120515). It was partially supported by the ACTRI (NIH UL1TR001442). T.K. was supported by NIH grants DK099205, AA028550, DK101737, AA011999, DK120515, AA029019, DK091183; C.K.G by NIH grants DK091183 and HL147835. T.D.T. was supported by NIH grants P30DK063491, T32DK007044, P30DK078392, the American Association for the Study of Liver Diseases (PNC23-216751) and the Center for Inflammation and Tolerance through the Cincinnati Children’s Research Foundation. R.L. received funding support from NCATS (5UL1TR001442), NIDDK (U01DK061734, U01DK130190, R01DK106419, R01DK121378, R01DK124318, P30DK120515), NHLBI (P01HL147835), the John C. Martin Foundation (RP124). J.M.O was supported by the Diabetes Research Center (P30DK063491) and Horton JPI MRA: Obesity and its metabolic complications (20175015). A.E.F was supported by the NIH grant R01DK113592. T.V.R was supported by grants from the Swiss National Science Foundation (P2BSP3_200177) and the Larry L. Hillblom Foundation (2023-D-012-FEL).
The study’s DOI is 10.1073/pnas.2405746121
END
Macrophage mix helps determine rate and fate of fatty liver disease
The white blood cells’ typical role is to promote inflammation and stimulate the immune response, but researchers say some actually appear to temper inflammatory conditions and improve healing
2024-08-22
ELSE PRESS RELEASES FROM THIS DATE:
Department of Energy announces $36 million to support energy-relevant research in underrepresented regions of America
2024-08-22
WASHINGTON, D.C. - Ensuring that scientific funding goes to states and territories that have typically received smaller fractions of federal research dollars in the past, the Department of Energy (DOE) today announced $36 million in funding for 39 research projects in 19 states via the Established Program to Stimulate Competitive Research (EPSCoR). The grants connect innovative ideas from scientists at eligible institutions with leading-edge capabilities at the DOE national laboratories.
Supporting scientists while building the expertise and capabilities critical for performing leading research ...
Analysis of 1,500 climate policies reveals only a small fraction achieved significant emission reductions
2024-08-22
A new machine learning analysis has revealed the most effective climate policies out of 1,500 implemented worldwide over the last two decades. Some of the success stories – numbered at about 63 – involve rarely studied policies and unappreciated policy combinations. “Our results provide a clear yet sobering perspective on the policy effort necessary for closing the remaining emissions gap of 23 billion tons carbon dioxide (CO2) by 2023,” write the authors. To achieve the Paris Agreement’s climate targets, it is essential to know which ...
Fatty-acid derived polymers yield recyclable and highly versatile adhesives
2024-08-22
Researchers have presented a new family of polymer adhesives that offer a sustainable and recyclable alternative to conventional polymer adhesives and can be used across a wide range of applications, from industrial adhesives to surgical superglues. The new chemical approach to aLA polymerization addresses the performance and environmental challenges of traditional polymers, providing environmentally friendly adhesive solutions. Polymer adhesives are ubiquitous in modern life and are widely used in many medical, consumer, and industrial products. Given this diversity, each adhesive material is often tailored ...
Governance needed to ensure biosecurity of biological AI models
2024-08-22
Concerns over the biosecurity risks posed by artificial intelligence (AI) models in biology continue to grow. Amid this concern, Doni Bloomfield and colleagues argue, in a Policy Forum, for improved governance and pre-release safety evaluations of new models in order to mitigate potential threats. “We propose that national governments, including the United States, pass legislation and set mandatory rules that will prevent advanced biological models from substantially contributing to large-scale dangers, such as the creation of novel or enhanced pathogens ...
Spontaneous transfer of mitochondrial DNA into the nuclear genomes in the human brain over the individual’s lifespan
2024-08-22
Somatic nuclear mitochondrial DNA (Numt) insertions are mito-nuclear gene transfer events that can arise in the germline and in cancer. This study shows that Numt insertions arise spontaneously and accumulate in brain tissues during development or over the human lifespan.
#####
In your coverage, please use this URL to provide access to the freely available paper in PLOS Biology: http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3002723
Article Title: Somatic nuclear mitochondrial DNA insertions are prevalent in the human brain and accumulate over time in fibroblasts
Author Countries: United States
Funding: see manuscript END ...
Cancer drug could treat early-stage Alzheimer’s disease, study shows
2024-08-22
UNIVERSITY PARK, Pa. — A type of drug developed for treating cancer holds promise as a new treatment for neurodegenerative diseases such as Alzheimer’s, according to a recent study by researchers at Penn State, Stanford University and an international team of collaborators.
The researchers discovered that by blocking a specific enzyme called indoleamine-2,3-dioxygenase 1, or IDO1 for short, they could rescue memory and brain function in models that mimic Alzheimer’s disease. The findings, published today (Aug. 22) in the journal Science, suggest that IDO1 inhibitors currently ...
Drugs that improve brain metabolism could help Alzheimer’s patients
2024-08-22
Among the many ways neuroscientists think Alzheimer’s disease may strip away brain function is by disrupting the glucose metabolism needed to fuel the healthy brain. In essence, declining metabolism robs the brain of energy, impairing thinking and memory.
Against that backdrop, a team of neuroscientists at the Knight Initiative for Brain Resilience at Stanford’s Wu Tsai Neurosciences Institute have zeroed in on a critical regulator of brain metabolism known as the kynurenine pathway. They hypothesize that that the kynurenine pathway is overactivated as a result of ...
Life after (feigned) death
2024-08-22
A new study led by scientists from the University of Bristol has revealed what animals do after they have feigned death in order to avoid being killed by a predator and what the context of this behaviour is.
Many animals, as a last-ditch defence, become motionless after being contacted by a predator.
This behaviour is so common that it's recognised in such phrases as “playing possum”. It is even said to occur in humans in extreme circumstances.
In previous studies, carried out by the same team using antlion larvae, scientists noticed that they become motionless after being individually handled.
At one point ...
Fisheries research overestimates fish stocks
2024-08-22
Many fish stocks around the world are either threatened by overfishing or have already collapsed. One of the main reasons for this devastating trend is that policymakers have often ignored the catch limits calculated by scientists, which were intended to be strict thresholds to protect stocks. But it has now become clear that even these scientific recommendations were often too high.
In the European Union (EU), for example, fisheries are primarily managed through allowable catch limits, known as quotas, which are set by the European ...
AI tackles one of the most difficult challenges in quantum chemistry
2024-08-22
New research using neural networks, a form of brain-inspired AI, proposes a solution to the tough challenge of modelling the states of molecules.
The research shows how the technique can help solve fundamental equations in complex molecular systems.
This could lead to practical uses in the future, helping researchers to prototype new materials and chemical syntheses using computer simulation before trying to make them in the lab.
Led by Imperial College London and Google DeepMind scientists, the study is published today in Science.
Excited molecules
The team investigated the problem of understanding ...
LAST 30 PRESS RELEASES:
Training to improve memory
Are patients undergoing surgery for early-stage cancer at risk of persistent opioid use?
Black youth, especially Black girls, use mental health services less than their White peers
Canada must protect youth from sports betting advertising
First-in-human trial shows promising results for DLL3-targeted antibody-drug conjugate SHR-4849 in relapsed small cell lung cancer
Ifinatamab deruxtecan demonstrates high response rate in previously treated extensive-stage small cell lung cancer: Phase 2 IDeate-Lung01 trial
Higher blood pressure in childhood linked to earlier death from heart disease in adulthood
AI helped older adults report accurate blood pressure readings at home
High blood pressure in childhood and premature cardiovascular disease mortality
Zidesamtinib shows durable responses in ROS1 TKI pre-treated NSCLC, including patients with CNS disease and ROS1 G2032R mutations
Crizotinib fails to improve disease-free survival in resected early-stage ALK+ NSCLC
Ivonescimab plus chemotherapy improves progression-free survival in patients with EGFR+ NSCLC following 3rd-generation EGFR-TKI therapy
FLAURA2 trial shows osimertinib plus chemotherapy improves overall survival in eGFR-mutated advanced NSCLC
Aumolertinib plus chemotherapy improves progression-free survival in NSCLC with EGFR and concomitant tumor suppressor genes: ACROSS 2 phase III study
New antibody-drug conjugate shows promising efficacy in EGFR-mutated NSCLC patients
Iza-Bren in combination with osimertinib shows 100% response rate in EGFR-mutated NSCLC, phase II study finds
COMPEL study shows continuing osimertinib treatment through progression with the addition of chemotherapy improves progression-free survival in EGFR-mutated NSCLC
CheckMate 77T: Nivolumab maintains quality of life and reduces symptom deterioration in resectable NSCLC
Study validates AI lung cancer risk model Sybil in predominantly Black population at urban safety-net hospital
New medication lowered hard-to-control high blood pressure in people with chronic kidney disease
Innovative oncolytic virus and immunotherapy combinations pave the way for advanced cancer treatment
New insights into energy metabolism and immune dynamics could transform head and neck cancer treatment
Pennington Biomedical’s Dr. Steven Heymsfield named LSU Boyd Professor – LSU’s highest faculty honor
Study prompts new theory of human-machine communication
New method calculates rate of gene expression to understand cell fate
Researchers quantify rate of essential evolutionary process in the ocean
Innovation Crossroads companies join forces, awarded U.S. Air Force contract
Using new blood biomarkers, USC researchers find Alzheimer’s disease trial eligibility differs among various populations
Pioneering advances in in vivo CAR T cell production
Natural medicines target tumor vascular microenvironment to inhibit cancer growth
[Press-News.org] Macrophage mix helps determine rate and fate of fatty liver diseaseThe white blood cells’ typical role is to promote inflammation and stimulate the immune response, but researchers say some actually appear to temper inflammatory conditions and improve healing