New research suggests that adhering to a high-fat, low-carbohydrate diet, commonly known as a 'keto diet,' could significantly elevate the risk of developing liver cancer within two decades. While proponents of the keto diet claim it facilitates rapid weight loss without hunger, experts now indicate that such fatty diets can fundamentally alter liver cells, making them more vulnerable to cancerous transformation.

US scientists have discovered that repeated exposure of the liver to a high-fat diet causes its cells to revert to a more primitive state. This cellular shift, while aiding survival under the stress of excess fat, simultaneously increases susceptibility to disease. Professor Alex Shalek, director of the Institute for Medical Engineering and Sciences and a study co-author, explained, "If cells are forced to deal with a stressor such as a high-fat diet over and over again, they will do things that will help them to survive, but at the risk of increased susceptibility to tumorigenesis [when normal cells mutate and become cancerous]." The research team hopes that by identifying and targeting these early cellular changes, doctors may be able to reduce the risk of tumor formation in vulnerable individuals.

A keto diet is characterized by an almost complete avoidance of carbohydrates, pushing the body into a state of ketosis where it burns stored fat for energy, leading to weight loss. Carbohydrates are essential macronutrients found in grains, starchy vegetables, and fruits. A typical keto diet often comprises 75 percent fat, 20 percent protein, and only 5 percent carbohydrates, starkly contrasting with the NHS's healthy balanced diet advice, which advocates for 30 percent fat, 15 percent protein, and over 50 percent carbohydrates.

High-fat diets have long been associated with steatotic liver disease, a condition where excess fat accumulates in the liver, leading to inflammation, potential liver failure, and ultimately cancer. In a study published in the journal *Cell*, researchers fed mice a high-fat diet and used cell-sequencing to analyze the liver's response. Initially, liver cells called hepatocytes activated genes that promoted their survival, reducing cell death and encouraging growth. Concurrently, however, genes crucial for normal liver function were suppressed. Constantine Tzouanas, a Harvard-MIT graduate and study co-author, described this as a "trade-off, prioritising what's good for the individual cell to stay alive in a stressful environment, at the expense of what the collective tissue should be doing." By the conclusion of the study, nearly all mice on the high-fat diet had developed liver cancer.

The researchers found that when liver cells adapt in this manner, they become more prone to becoming cancerous if a damaging mutation occurs later. Tzouanas noted, "These cells have already turned on the same genes that they're going to need to become cancerous. Once a cell picks up the wrong mutation, then it's really off to the races and they've already got a head start on some of those hallmarks of cancer." Following these observations in mice, the team investigated people with various stages of liver disease. They found that over time, genes necessary for normal liver function deteriorated, while those linked to cell survival thrived, allowing them to accurately predict patient survival outcomes. Patients with higher expression of these 'pro-cell-survival' genes, activated by a high-fat diet, had shorter survival times after tumor development. Similarly, lower expression of genes supporting normal liver functions correlated with reduced survival.

The scientists emphasized that while most mice developed cancer within a year, this process is considerably slower in humans, unfolding over approximately 20 years. However, this timeframe can fluctuate based on lifestyle factors such as alcohol consumption and overall health, with excessive drinking and viral infections accelerating liver cells towards an 'immature' state, thereby increasing cancer risk. This heightened risk arises because less mature liver cells are more likely to become cancerous if a damaging mutation occurs. The team plans to further investigate whether this damage can be reversed through healthier diets or by using GLP-1 weight loss drugs like Mounjaro.

Despite multiple studies highlighting the potential dangers, the keto diet has gained immense popularity, partly due to endorsements from celebrities like Gwyneth Paltrow, Jennifer Aniston, Halle Berry, and Kourtney Kardashian. Historically, liver disease was largely confined to the elderly and heavy drinkers, but it is now rapidly increasing among younger adults. The British Liver Trust estimates that the condition may affect one in five people in the UK, with some experts warning the true figure could be as high as 40 percent. Alarmingly, around 80 percent of those affected remain undiagnosed, as the disease often presents with no obvious symptoms or symptoms that are mistaken for less serious issues. Approximately one in four patients will progress to a more advanced form of the disease, leading to irreversible liver scarring, organ failure, and cancer. Experts are optimistic that weight loss injections like Mounjaro could revolutionize liver disease treatment by helping the liver burn excess fat, which contributes to disease risk. Prof Shalek concluded, "We now have all these new molecular targets and a better understanding of what is underlying the biology, which could give us new angles to improve outcomes for patients."