PCSK9 and APOA4: the dynamic duo in TMAO-induced cholesterol metabolism and cholelithiasis
2025-03-25
(Press-News.org) Background and Aims
Cholesterol synthesis and gallstone formation are promoted by trimethylamine-N-oxide (TMAO), a derivative of trimethylamine, which is a metabolite of gut microbiota. However, the underlying mechanisms of TMAO-induced lithogenesis remain incompletely understood. This study aimed to explore the specific molecular mechanisms through which TMAO promotes gallstone formation.
Methods
Enzyme-linked immunosorbent assays were used to compare serum concentrations of TMAO, apolipoprotein A4 (APOA4), and proprotein convertase subtilisin/kexin type 9 (PCSK9) between patients with cholelithiasis and normal controls. A murine model of TMAO-induced cholelithiasis was employed, incorporating assays of gallstone weight and bile cholesterol content, along with RNA sequencing of murine hepatic tissue. A TMAO-induced AML12 hepatocyte line was constructed and transfected with targeted small interfering RNAs and overexpression plasmids. In vivo and in vitro experiments were performed to determine the expression and regulation of genes related to cholesterol metabolism.
Results
Serum TMAO and PCSK9 levels were elevated, whereas APOA4 levels were reduced in patients with cholelithiasis. Furthermore, our murine model demonstrated that TMAO upregulated hepatic expression of PCSK9, 3-hydroxy-3-methylglutaryl-CoA reductase, and ATP-binding cassette sub-family G member 5/8, while reducing APOA4 expression, thereby modulating cholesterol metabolism and promoting lithogenesis. PCSK9 and APOA4 were identified as key regulatory genes in the cholesterol metabolic pathway. PCSK9 knockdown increased APOA4 expression, while APOA4 overexpression led to reduced PCSK9 expression.
Conclusions
We have discovered that TMAO dysregulates cholesterol metabolism by initiating a feedback loop, upregulating PCSK9 expression, and downregulating APOA4 expression in murine hepatic tissue, thereby promoting gallstone formation. In clinical practice, hyperlipidemia, a risk factor for cardiovascular diseases, also promotes gallstone formation, which should warrant attention. Regulation of blood lipid levels is necessary for patients with cholelithiasis. Targeting PCSK9 and APOA4 may represent a promising approach for the prevention and treatment of cholelithiasis.
Full text
https://www.xiahepublishing.com/2310-8819/JCTH-2024-00403
The study was recently published in the Journal of Clinical and Translational Hepatology.
The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study’s novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.
Follow us on X: @xiahepublishing
Follow us on LinkedIn: Xia & He Publishing Inc.
END
[Attachments] See images for this press release:
ELSE PRESS RELEASES FROM THIS DATE:
2025-03-25
When the plasma inside a fusion system starts to misbehave, it needs to be quickly cooled to prevent damage to the device. Researchers at Commonwealth Fusion Systems believe the best bet is a massive gas injection: essentially, a well-timed, rapid blast of cooling gas inside their fusion system, which is known as SPARC. But how many gas valves does it take to quickly tame a plasma that is hotter than the sun? The team has to strike the perfect balance: with too few valves, some parts of SPARC might overheat. With too many, valuable space inside the ...
2025-03-25
About 4.5 million workers in the United States quit their jobs in 2022, continuing a trend that began after the 2007 Great Recession. Despite better labor conditions and the pandemic’s decline, many adults are still less willing to return to work compared to previous recessions, making it harder for companies to attract and retain top talent. Moreover, voluntary turnover – when an employee quits their job as opposed to being fired or laid off – costs U.S. businesses more than $1 trillion each year.
Beyond recruitment and training expenses, turnover disrupts operations, damages customer relationships, and often leads to further departures. Replacing an employee ...
2025-03-25
LOS ANGELES — City of Hope®, one of the largest and most advanced cancer research and treatment organizations in the U.S. with its National Medical Center named top 5 in the nation for cancer by U.S. News & World Report, has opened a phase 1 trial seeking to one day transform rectal cancer from a mostly radiation-resistant disease to one that can be cured using radiation and chemotherapy.
“Many cancers are cured through radiation therapy alone or radiation in combination with chemotherapy, including — but not limited to — prostate, head and ...
2025-03-25
The rate of maternal mortality related to cardiovascular causes more than doubled between 1999 and 2022 in the United States, according to a study being presented at the American College of Cardiology’s Annual Scientific Session (ACC.25).
The finding is concerning, especially as the U.S. has the highest overall rate of maternal mortality among all developed countries, researchers said. Since cardiovascular problems are a leading cause of death around the time of pregnancy and childbirth, the new findings shed light on the drivers behind recent trends and draw attention to particularly high rates of mortality seen among ...
2025-03-25
Tiny fragments of plastic have become ubiquitous in our environment and our bodies. Higher exposure to these microplastics, which can be inadvertently consumed or inhaled, is associated with a heightened prevalence of chronic noncommunicable diseases, according to new research being presented at the American College of Cardiology’s Annual Scientific Session (ACC.25).
Researchers said the new findings add to a small but growing body of evidence that microplastic pollution represents an emerging health threat. In terms of its relationship with stroke risk, for example, microplastics concentration ...
2025-03-25
Compared with those who spent most of their time in a single room, people with heart failure with preserved ejection fraction (HFpEF) who were able to travel outside of their home without assistance were significantly less likely to be hospitalized or die within a year, according to a study being presented at the American College of Cardiology’s Annual Scientific Session (ACC.25). The findings underscore the value of supporting holistic care and encouraging people with heart failure to maintain an active lifestyle and engage with others ...
2025-03-25
In addition to causing several types of cancer, human papillomavirus (HPV) appears to bring a significantly increased risk of heart disease and coronary artery disease, according to a study being presented at the American College of Cardiology’s Annual Scientific Session (ACC.25).
Evidence that HPV is linked with heart disease has begun to emerge only recently. This new study is the first to assess the association by pooling data from several global studies, totaling nearly 250,000 patients. Its findings bolster the evidence that a significant relationship exists ...
2025-03-25
A new peer-reviewed studyi* published in Frontiers in Nutrition provides compelling evidence that pork can play a beneficial role in sustainable diets. The research, conducted by scientists at William & Mary, modeled the environmental and economic impacts of substituting various protein sources with pork in a nationally representative sample of U.S. adults.
The findings suggest that pork performs similarly to poultry, seafood, eggs and legumes across key sustainability and agricultural resource indicators with a ± 1% change in land use, fertilizer nutrient use and pesticide use.
Modeled ...
2025-03-25
Imagine a robot that can walk, without electronics, and only with the addition of a cartridge of compressed gas, right off the 3D-printer. It can also be printed in one go, from one material.
That is exactly what roboticists have achieved in robots developed by the Bioinspired Robotics Laboratory at the University of California San Diego. They describe their work in an advanced online publication in the journal Advanced Intelligent Systems.
To achieve this feat, researchers aimed to use the simplest technology available: a desktop ...
2025-03-25
Mill Valley, CA – March 25, 2025 – The SynGAP Research Fund (SRF) dba Cure SYNGAP1 501(c)(3) announced a $130,000 grant to Dr. Vikaas Sohal at The Regents of The University of California, San Francisco. The grant supports research into new therapies for reversing cognitive deficits in SYNGAP1-related disorders (SRD) by enhancing key brain functions.
Dr. Sohal’s research focuses on cognitive flexibility—the ability to adapt behavior in response to environmental changes—a ...
LAST 30 PRESS RELEASES:
[Press-News.org] PCSK9 and APOA4: the dynamic duo in TMAO-induced cholesterol metabolism and cholelithiasis
