Tag: metabolic-associated fatty liver disease

Categories : CancerTags :

High-fat Diets are ‘Ticking Time Bombs’ for Liver Cancer

On By ModernMedia
These images show slices of mouse liver under the microscope, with tumours outlined in yellow and green indicating the expression of different proteins within cells. The left column is a control group. In the centre column, the protein detected (TBG-Cre) is expressed in all liver cells, so the entire image appears green. In the right column, the protein detected (p21-Cre) is only expressed in senescent liver cells. Because green is only visible within the tumour area, the results show that liver tumours originate from previously senescent liver cells. Photo credit: UC San Diego Health Sciences

A new study on the development of liver cancer reveals a complex interplay between cellular metabolism and DNA damage that drives the progression of fatty liver disease to cancer. The findings, published in Nature, 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. 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.

“Going from fatty liver disease to MASH to liver cancer is a very common scenario, and the consequences can be deadly,” said Michael Karin, PhD, Distinguished Professor in the Department of Pharmacology at UC San Diego School of Medicine. MASH ends up destroying the liver, or leading to often-fatal liver cancer, but little is know of the process at the subcellular level.

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.

“A poor, fast-food diet can be as dangerous as cigarette smoking in the long run. People need to understand that bad diets do far more than just alter a person’s cosmetic appearance. They can fundamentally change how our cells function, right down to their DNA.”

Michael Karin, PhD

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 tumour DNA indicate that they originate from liver cells damaged by MASH, emphasising a direct link between diet-induced DNA damage and the development of cancer,” added study co-author Ludmil Alexandrov, PhD, 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.

“There are a few possibilities for how this could be leveraged into a future treatment, but it will take more time and research to explore these ideas,” said Karin. “One hypothesis is that a high-fat diet could lead to an imbalance in the raw materials our cells use to build and repair DNA, and that we could use drugs or nutri-chemicals to correct these imbalances. Another idea is developing new antioxidants, much more efficient and specific than the ones we have now, and using those could help block or reverse the cellular stress that causes DNA damage in the first place.”

In addition to opening these new avenues of treatment for liver cancer, the study also offers new insight into the relationship between aging and cancer.

“We know that aging increases the risk of virtually all cancers and that aging is associated with cellular senescence, but this introduces a paradox since senescence is supposed to guard against cancer,” said Karin. “This study helps reveal the underlying molecular biology that allows cells to re-enter the cell cycle after undergoing senescence, and we believe that similar mechanisms could be acting in a wide range of cancers.”

The findings also help directly quantify the detrimental effects of poor diet on cellular metabolism which, according to Karin, could be used to help guide public health messaging related to fatty liver disease.

“A poor, fast-food diet can be as dangerous as cigarette smoking in the long run,” said Karin. “People need to understand that bad diets do far more than just alter a person’s cosmetic appearance. They can fundamentally change how our cells function, right down to their DNA.”

Source: University of California – San Diego

Categories : Metabolic DisordersTags :

Oestrogen’s Protection against Fatty Liver Points to New Drug Treatment

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Photo by The Creative Exchange on Unsplash

New research from Karolinska Institutet shows how oestrogen protects against MASLD, a fatty liver disease on the increase in the obesity epidemic. The study, published in Molecular Systems Biology, shows how a new drug under development could become a future treatment for fatty liver disease and liver cancer.

The global obesity epidemic has resulted in a dramatic increase in fatty liver, a disease in which fat that does not fit into fat cells is stored in liver cells instead.

Since last year, fatty liver due to obesity (and not excessive alcohol consumption) is known as MASLD (metabolic dysfunction-associated steatotic liver disease). According to previous research, as many as one in three adults are affected by some degree of MASLD, which in the worst cases can develop into cirrhosis and liver cancer.

Protection until menopause

However, the disease is very unevenly distributed between the sexes, with a large majority of affected individuals being men.

“Women have a natural protection until menopause due to the female sex hormone oestrogen,” explains study leader Claudia Kutter, senior researcher at the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet.

Although women’s protection has been known for some time, the mechanism behind the protective effect has been less clear. Now Claudia Kutter’s research team may have found the answer.

Through genetic analyses of mice of both sexes fed a high-fat diet, with some of the male mice also receiving oestrogen, the researchers were able to identify a key protein in the development of fatty liver. 

The protein, called TEAD1, was found to play an overall role in regulating how liver cells absorb fat. Blocking TEAD1 protected liver cells from the harmful accumulation of fat. Mice receiving oestrogen treatment had lower TEAD1 activity and less fat accumulation in the liver.

New drug under development

In the next step, the researchers tested blocking TEAD1 in human liver cells with the same result. The fact that this was possible at all, however, was a bit of luck.

“It turned out that a pharmaceutical company is developing an anti-cancer drug that blocks TEAD1, which allowed us to test our hypothesis,” says Claudia Kutter.

The fact that TEAD1 is also involved in cancer does not worry her, quite the contrary.

“Since the activity of TEAD proteins is elevated in cancer, blocking TEAD at an early stage can also be positive from a cancer point of view,” she says. “Patients suffering from liver cancer are currently diagnosed very late. If the patient is given this drug early in the process to protect against fatty liver, it can hopefully also prevent the development of liver cancer.”

The pharmaceutical company will now start clinical trials of the drug as a protection against fatty liver disease, while Claudia Kutter’s research team will continue researching further ways to tackle the disease.

“We want to focus on how to find the disease earlier and identifying new treatment targets,” she says. “Different approaches may be needed for different patients depending on their gender and hormonal status.”

Source: Karolinska Institutet

Categories : Gastrointestinal Metabolic DisordersTags :

Targeting Inflammation may Not Help Reduce Liver Fibrosis in MAFLD

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Researchers at UCLA Health uncovered new information about the role inflammation plays in mitigating liver fibrosis, which is associated with metabolic-associated fatty liver disease (MAFLD).  While inflammation in the liver has long been considered a prerequisite to developing liver fibrosis, the scarring and thickening of tissue that can impair the liver’s ability to function, this new research, published in the Journal of Clinical Investigation, suggests that reducing inflammation may not influence the extent of fibrosis. 

“Liver fibrosis is the critical feature that creates chronic liver disease and liver cancer. If we can keep fibrosis in check then we can meaningfully impact liver disease,” said Tamer Sallam, MD, corresponding author of the study and vice chair and associate professor in the department of medicine at the David Geffen School of Medicine at UCLA. 

“For decades we have believed that targeting inflammation is one of the most important ways to reduce MAFLD. But this new research indicates that inflammation, while still important, may not be the main driver of fibrosis.”

The study looked specifically at a protein called lipopolysaccharide binding protein (LBP), which is involved in the body’s immune response, and how LBP functions in mice. Findings showed that mice without LBP in their liver cells had lower levels of liver inflammation and better liver function but no change in fibrosis. 

In addition to mouse models, the researchers also studied genetic analyses from large human datasets and human tissue samples from MAFLD patients at different stages in the disease, to examine the consequence of loss of LBP function. The evidence combined showed that the LBP does not alter scar tissue markers. 

Sallam indicated a need to further explore how LBP influences inflammation and whether other factors can offer a more potent reduction in inflammation and have an impact on reducing fibrosis. 

“Reducing scar burden is one of the holy grails in the treatment of advanced liver diseases,” Sallam said. “These results suggest that certain ways of targeting inflammation may not be a viable option and that more directed therapies against other pathways could help us better target fibrosis and improve outcomes for patients.”

Source: UCLA Health