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Loss of FBP1 protein behind MASH progression to liver cancer: Study
2025-01-06 - 2025-01
A molecular system controlled by a protein called FBP1 is responsible for how liver cells damaged by MASH — fully, metabolic dysfunction-associated steatohepatitis, a severe form of fatty liver disease — grow into cancer cells.
That’s according to the findings of a new study, led by researchers at the University Of California San Diego School Of Medicine, that shed light on the mechanisms underlying the progression of MASH — which is often associated with a diet high in fats and fast food — to liver cancer.
“Going from fatty liver disease to MASH to liver cancer is a very common scenario, and the consequences can be deadly,” Michael Karin, PhD, a UC San Diego professor and co-author of the study, said in a university press release. “When you have MASH, you either end up destroying your liver and then you need a new liver, or you progress to frequently fatal liver cancer, but we still don’t understand what’s happening at the subcellular level during this process.”
Study coauthor Ludmil Alexandrov, PhD, noted that diet is tied to liver cell damage. “Comprehensive genomic analyses of tumour DNA indicate that [these cells] originate from liver cells damaged by MASH, emphasizing a direct link between diet-induced DNA damage and the development of cancer,” said Alexandrov, an associate professor of cellular and molecular medicine and bioengineering at UC San Diego and member of university’s Moores Cancer Centre.
FBP1 protein key in cancer development, researchers find
Fatty liver disease is a disorder marked by the abnormal build-up of fat in the liver. In severe cases, this can progress to MASH, which is marked by liver inflammation and scarring. It’s well-established that MASH increases the risk of developing hepatocellular carcinoma (HCC), the most common form of liver cancer. However, the precise biology by which MASH leads to HCC remains not fully understood. It’s previously been shown that a diet with too much fat and sugar — the type of diet that can lead to the development of MASH — can cause damage to liver cells’ DNA and drive the cells into a state called senescence. During senescence, cells are alive and metabolically active, but they don’t actively divide to make new cells. Senescence is a normal response to cellular stress. In theory, stopping dividing gives the cell time to recuperate and repair damage, which should ultimately reduce the risk of the cell acquiring mutations and growing out of control to cause a cancer.
Most liver cancers arise directly from cells in senescence: Study
Through an in-depth battery of experiments, the researchers demonstrated that senescent liver cells can lose FBP1’s activity. When FBP1 is lost, another cell growth-suppressing protein called p53 is also lost, while the activity of AKT and NRF2 — two proteins that drive cell growth — is increased. This molecular dysregulation ultimately leads healthy senescent liver cells to grow into cancer cells.This finding has posed a conundrum for researchers: I
Why Patients Diagnosed With Fatty Liver Disease Must Exercise Every Day
2025-01-07 - 2025-01
What is fatty liver disease? The liver is one of the most important organs of the body, but many people suffer from, what is known as, fatty liver disease. Also known as hepatic steatosis, fatty liver is a condition where excess fat builds up in the liver cells. There are two main types of fatty liver disease: alcoholic fatty liver disease (AFLD), which is caused by excessive alcohol consumption, and non-alcoholic fatty liver disease (NAFLD), which is not related to alcohol consumption at all, but rather other factors are at play. This condition affects millions of people around the world, and it is important to know everything about it, including what causes it and how it can be prevented/managed. According to doctors, fatty liver disease is more common in people over 50. Additionally, men are more likely to develop fatty liver disease. The presence of other health conditions, such as polycystic ovary syndrome (PCOS) or sleep apnea, are supposed to increase the risk of fatty liver disease.
Read on to find out everything about it. Before starting any new exercise routine, consult with your doctor to ensure that it is safe and suitable for your condition. Begin with gentle exercises and gradually increase intensity and duration. Listen to your body, and rest when needed; avoid overexerting yourself. Stay hydrated by drinking plenty of water before, during, and after exercise. The above-mentioned information is generic. It is not a substitute for a qualified medical opinion.
Should Fatty Liver Patients Exercise?
Exercising is recommended for fatty liver patients. They must, however, check with their doctor first. Here are some benefits of exercise for such patients:
• Improved insulin sensitivity: Exercising regularly can help reduce insulin resistance, which is a common issue in fatty liver disease.
• Liver fat reduction: It is also said that exercising can decrease liver fat and inflammation in people with fatty liver disease.
• Weight loss: Exercise can help with weight loss, which is often recommended for fatty liver patients, especially those who are obese.
• Improved overall health: Regular physical activity can reduce the risk of developing other health problems, such as heart disease and type 2 diabetes, and improve overall health.
Study reveals how fatty liver disease leads to liver cancer
2025-01-02 - 2025-02
Scientists at University of California San Diego School of Medicine have shed new light on the development of liver cancer, the sixth most frequently diagnosed cancer and fourth leading cause of cancer deaths worldwide. The study, published in Nature, reveals a complex interplay between cellular metabolism and DNA damage that drives the progression of fatty liver disease to cancer. The findings suggest new paths forward for preventing and treating liver cancer and have significant implications on our understanding of cancer's origin and the effects of diet on our DNA.The incidence of the most common form of liver cancer, hepatocellular carcinoma (HCC), has grown by 25-30% in the past two decades, with much of the growth attributed to the dramatic rise in fatty liver disease, which currently affects 25% of adult Americans. About 20% of individuals with fatty liver disease have a severe form of the disease, called metabolic dysfunction-associated steatohepatitis (MASH), that greatly increases the risk of HCC. However, how MASH transitions to liver cancer is not well understood. The researchers used a combination of mouse models and human tissue specimens and databases to demonstrate that MASH-inducing diets, which are rich in fat and sugar, cause DNA damage in liver cells that causes them to go into senescence, a state in which cells are still alive and metabolically active but can no longer divide. Senescence is a normal response to a variety of cellular stressors. In a perfect world, senescence gives the body time to repair damage or eliminate the damaged cells before they're allowed to proliferate more widely and become cancerous.
However, as the researchers discovered, this isn't what happens in liver cells, also known as hepatocytes. In hepatocytes, some damaged cells survive this process.These cells are, according to Karin, "like ticking time bombs that could start proliferating again at any point and ultimately become cancerous."Comprehensive genomic analyses of tumor DNA indicate that they originate from liver cells damaged by MASH, emphasizing a direct link between diet-induced DNA damage and the development of cancer," added study co-author Ludmil Alexandrov, Ph.D., associate professor of cellular and molecular medicine and bioengineering at UC San Diego and member of UC San Diego Moores Cancer Center. The findings suggest that developing new drugs to prevent or reverse DNA damage could be a promising therapeutic approach for preventing liver cancer, particularly in people with MASH.
Three-pronged treatment improves prognosis for inoperable liver cancer
2025-01-10 - 2025-01
Two independent studies reveal that disease progression is delayed by combining two targeted therapies with the traditional approach that cuts off tumor nutrition pathways
If decades and decades of cancer research have shown anything, it is that there is no magic bullet to defeat cancer. he scientific community is increasingly certain that the success of the fight against the most aggressive tumors lies in attacking multiple fronts simultaneously to prevent the escape of tumor cells that enable disease progression. Two new, independent studies published on Wednesday in The Lancet explore this strategy in the context of liver cancer and confirm that combining two targeted therapies with a traditional treatment that disrupts the tumor’s nutrient supply can delay disease progression. Both studies, which are phase III trials, evaluate different drug combinations, but share a common strategy: attacking the tumor from different fronts to maximize efficacy.
One of the studies, called LEAP-012, employed a three-pronged therapeutic approach against an intermediate-stage tumor that, while not yet spread to other parts of the body, is too large for surgical removal: non-metastatic, non-resectable hepatocellular carcinoma. In a clinical trial, researchers from Idibaps-Clínic in Barcelona, showed that adding slenvatinib (a molecular therapy) and pembrolizumab (an immunotherapy) to traditional chemoembolization (which blocks the tumor’s blood supply) improves progression-free survival — the time a patient lives without tumor progression. Although the results of the clinical trial are modest — the progression-free survival increased from 10 months with chemoembolization alone to 14.6 months with the three-pronged approach — the findings mark a breakthrough in a tumor type that has seen no significant therapeutic advances in two decades. Nearly 500 patients participated in the research.
In the other study (EMERALD-1), led by the Clínica Universidad de Navarra (CUN), researchers also tested a three-pronged strategy for inoperable liver cancer. In a trial with 616 patients, they added a combination of durvalumab (an immunotherapy) and bevacizumab (a drug that blocks blood vessel growth) to conventional chemoembolic therapy, and found that it slowed disease progression. The combination of the two targeted therapies delayed cancer progression by 6.8 months compared to the participants who received a placebo. Every year, around 6,000 cases of liver cancer are diagnosed in Spain. In the vast majority of cases (90%), patients have a history of cirrhosis, often due to hepatitis B or C, alcohol abuse, or metabolic diseases. Josep Maria Llovet, a professor of Medicine and Hepatology at the University of Barcelona and ICREA professor at Idibaps, notes that 30% of tumors are diagnosed at early stages, when the typical treatment involves removal of the tumor, liver transplant, or radioembolization (microwaves used to eliminate small tumors).
However, other cases ar
Antihistamines offer new hope for erythropoietin protoporphyria-related liver disease
2025-01-21 - 2025-01
In the present study, the methods involved high-throughput drug screening using a zebrafish model to identify compounds that reduce PP-IX accumulation. Transgenic zebrafish larvae were injected with ?-aminolevulinic acid (ALA) and deferoxamine (DFO), inducing PP-IX overproduction.
Fluorescence imaging was used to assess liver PP-IX levels, leading to the identification of chlorcyclizine (CCZ) as a promising compound. Validation studies were conducted in primary mouse hepatocytes treated with ALA and DFO and in two mouse models of EPP- the Ferrochelatase mutant 1 with a pedigree from Pas (Fechm1Pas) mice and mice fed with a porphyrin genic diet containing 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC).
Plasma, liver, and stool PP-IX levels were measured using fluorescence, and histological analysis assessed liver morphology. Nuclear translocation of key bile acid receptors, including constitutive androstane receptor and farnesoid-X receptor, was analyzed, along with the expression of PP-IX clearance transporters. Knockdown experiments targeting bile salt export pump (BSEP) and multidrug resistance-associated protein-4 (MRP4) explored transporter roles in PP-IX handling.
The study further investigated histamine receptor (H) activity using antihistamines, assessing their effect on PP-IX levels and protein aggregation. Data were statistically analyzed to confirm the efficacy of CCZ in lowering PP-IX and alleviating EPP-related liver damage, highlighting the potential therapeutic value of antihistamines.
Conclusion
To summarize, only afamelanotide (SCENESSE®), an ?-melanocyte-stimulating hormone analog, has been Food and Drug Administration (FDA)-approved to address skin symptoms in EPP, leaving liver complications untreated. CCZ, an H1-antihistamine, was identified through drug screening as a potent PP-IX reducer. CCZ decreased PP-IX levels and alleviated liver injury in female experimental models by inducing bile excretion through activation of CAR/MRP4 and FXR/BSEP pathways. It also inhibited histamine-mediated PP-IX accumulation, reduced protein aggregation, and oxidative stress.
These findings suggest CCZ and other antihistamines hold promise as safe and effective treatments for EPP-related liver disease.
A Surprising Fix for a Personality-Changing Liver Disease
2025-01-22 - 2025-01
“Our bodies have a finely tuned, built-in detoxifying system: It's called our liver, and it can detoxify our bodies better than any cleanse or fast.” —Harley PasternakThe community of microbes in our gut, like any other neighborhood, requires a trash service. Some wastes, like ammonia, can build up in our gut and make life uncomfortable for both us and our microbes. Fortunately, our liver continually sweeps the ammonia up, repackages it as urea, and sends it off to our kidneys to pee out. Problem solved. But if the liver is badly damaged and can’t take out the trash, then the ammonia will build up in the body, including the brain. That’s bad news. Although the damage is mostly temporary, it is often not subtle. It can lead to confusion, disorientation, erratic behavior, mood swings, hallucinations, and personality changes. It’s not new. Hippocrates wrote that his advanced liver patients were the worst: combative and noisy.
This is hepatic encephalopathy (HE), and it can be devastating. A common precursor is cirrhosis, the leading cause of liver-related mortality. Although alcohol is a major contributor to cirrhosis, recent research has shown that there is a microbial aspect to it as well. The gut microbiome is disturbed in cirrhosis patients, producing toxins that may exacerbate the disease.Almost half of all cirrhosis patients go on to develop HE. If untreated, half of those patients won’t live out the year. You might think a liver transplant would be called for, but people with HE are considered high risk and put on the back burner. Instead, as we’ll see, there’s another kind of transplant that may help. We have long known that HE is a disease that straddles the gut-microbe-liver-brain axis. In fact, the microbial angle to HE was discovered when doctors realized that antibiotics could improve its symptoms. By killing ammonia-producing microbes, antibiotics deal with the trash at the source. However, as is often the case with antibiotics, it can create a lot of collateral damage to beneficial bacteria.A less destructive treatment involves probiotics. These can help balance the gut microbiome to favor more fastidious microbes that produce less ammonia. Still, some HE patients are unable to totally renew their microbiome and can suffer relapses.
Responding to Rise of Metabolic Liver Disease in Connecticut
2025-01-28 - 2025-01Metabolic liver disease is on the rise in Connecticut. More than a third of people in the state have a diagnosis of metabolic dysfunction-associated steatotic liver disease (MASLD) or a more severe form of the disease, called metabolic dysfunction-associated steatohepatitis (MASH). People with these diseases (previously referred to as nonalcoholic fatty liver disease; NAFLD) have excess fat inside liver cells, which ultimately results in loss of normal liver function. MASLD and MASH can lead to end-stage liver disease including cirrhosis, and liver cancer. The dramatic rise of MASLD and MASH in Connecticut and across the country is alarming,” said Wajahat Mehal, MD, DPhil, professor of medicine (digestive diseases). “It is especially concerning because our numbers only include those who have a formal diagnosis. Many other people across the state have the disease but are not receiving diagnosis, treatment or surveillance.”Mehal is the chair of a working group established by the Connecticut General Assembly to provide recommendations to increase awareness and education and improve public health infrastructure to respond to the increase in the prevalence of MASLD and MASH across the state. MASH is a leading cause of liver transplants and a common cause of chronic liver disease, yet there is little public awareness of this disease,” said Bubu Banini, MD, PhD, assistant professor of medicine (digestive diseases), who was co-chair of the working group. “There is a clear need for more state support to help increase public education and coordinate screening efforts to reduce the impact of MASH and MASLD. The working group developed 20 recommendations, which they shared with the Connecticut General Assembly Public Health Committee. Recommendations include: Establish an annual Connecticut Liver Health Day to bolster awareness, education, and advocacy around liver health. Establish new systems to screen people at high risk of MASH, including through electronic health records (EHRs) and non-invasive ultrasound technology in high-risk areas. Develop outreach programs to educate key audiences and stakeholders about the disease. Audiences include primary care providers, pediatricians, community health workers, teachers and school health workers, middle and high school students, and community organizations in Hispanic communities, among others. highlight several key points during educational efforts, including the role of moderate alcohol intake in increasing the likelihood and severity of liver disease Include chronic liver disease in the State Health Dashboard to provide visibility and awareness of the rise in prevalence of the disease.
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