Researchers have revealed the lethal impact of diets high in fat, which significantly contribute to the development of deadly cancers.

The liver is continuously burdened by unhealthy fats prevalent in processed foods, which constitute approximately 55% of the American diet. This eating habit not only fuels the nation’s 40% obesity rate but, as recent studies suggest, also causes extensive cellular harm.

Faced with this dietary onslaught, the liver enters a survival mode, temporarily halting its essential duties. These include filtering blood, metabolizing nutrients, eliminating toxins, and synthesizing crucial proteins and enzymes. Instead, the organ focuses solely on enduring the persistent dietary stress.

Over prolonged periods, liver cells gradually lose their capability to perform complex functions. They regress to a more basic state, operating just enough to avoid failure, but neglecting their critical roles in maintaining health.

Emerging research indicates that the molecular damage inflicted by chronic dietary stress, observable in liver tissue samples, can forecast the likelihood of liver cancer. This prediction can be made a decade before a tumor actually develops, in a disease that affects around 42,000 Americans and claims about 30,000 lives annually.

The survival mode environment is primed for the growth of cancer cells, as it involves shutting down tumor-suppressing genes and the clean-up crew that disposes of dead and dangerous cells, allowing them to grow, mutate, spread and eventually clump together to form tumors.

A real-time study by scientists at the Massachusetts Institute of Technology and Harvard University found that when mice eat high-fat diets, their liver cells undergo a slow reprogramming over 15 months.

Within just six months of a high-fat diet, stressed liver cells began priming for cancer. The biological ‘locks’ on DNA regions controlling cell growth and survival were opened, placing the genetic instructions for cancer on standby, a state of dangerous readiness established years before a tumor would appear. 

Every year, liver cancer is diagnosed in about 42,000 people in the United States, and it claims the lives of roughly 30,000 of them due to its aggressive nature (stock)

In humans with early fatty liver disease, these same early warnings were also observed, and their strength predicted which patients would develop liver cancer over a decade later. The research indicated the liver’s immediate coping mechanism for dietary stress inadvertently paves the way for future cancer development.

Millions of Americans adhere to a diet full of ultra-processed foods and saturated fats. A 2019 estimate based on reported dietary trends from 1999 to 2016, the share of calories that came from saturated fat rose from 11.5 percent to about 12 percent. National dietary guidelines recommend less than 10 percent.

Researchers wanted to understand how long-term stress on the liver from a poor diet can set the stage for hepatocellular carcinoma (HCC), the most common type of liver cancer, even before any tumors appear.

To do this, they studied a detailed model that mimics fatty liver that progresses to cancer, a common human disease, but without adding any external cancer-causing chemicals or genes.

HCC is often deadly when caught past stage one. Once the cancer has entered stage two, average life expectancy falls to two years or fewer. 

The study involved feeding normal mice a high-fat diet (HFD) over a long period, up to 15 months, to see how their livers would respond. 

This diet acted as a constant source of metabolic stress that mimicked the effects of chronic poor nutrition in humans.

Not only did liver cells seem to forget their normal jobs, but chronic stress also forced them to reactivate survival and early developmental genes, causing them to revert to a primitive, fetal-like state. 

The four panels show photographs of liver cells under the microscope. It shows that chronic metabolic stress caused by a high-fat diet causes scar-promoting immune cells to form organized, clustered hubs within the liver (dyed green), creating the local diseased ‘neighborhoods’ that drive progression toward cancer

This occurred while turning off genes that define a healthy liver cell, including the master switches that give the cell its identity, key enzymes for metabolism and important proteins that communicate with the immune system.

Those primitive, fetal genes are designed for one thing the rapid, flexible growth of liver cells. When they are turned back on in an adult liver, the cell regains the ability to divide quickly and ignore the normal spatial limits that keep tissue organized. This unchecked growth is a hallmark of tumors.

Once liver cells are thrown into this chaotic, primitive state, it becomes much easier for additional DNA damage, which accumulates naturally over time, to push them over the edge into full-blown cancer.

Crucially, this reprogramming also unlocks and makes accessible the regions of DNA that control growth and development. 

This means that a single genetic mutation can make the physical DNA instructions for cell growth and cancer easily readable and available to the cell’s machinery, setting the stage for those genes to be activated.

After discovering the dangerous liver cell reprogramming in mice fed a high-fat diet, the scientists wanted to know if these same changes happen in people and whether they predict human disease.

They analyzed banked liver tissue samples from human patients who had been diagnosed with fatty liver disease (Metabolic Dysfunction-Associated Steatotic Liver Disease, or MASLD) at various stages, from mild to severe, including some who later developed HCC.

They tested the human liver samples for the same molecular signatures they saw in the mice. Specifically, they looked for low levels of the protective enzyme HMGCS2, high activity of the ‘survival-mode,’ a surge in the activity of early-development gene programming and low activity of the genes for mature liver function.

They had access to patient medical records, which allowed them to link molecular data from a patient’s biopsy to what happened to that patient years later.

People with fatty liver disease showed the exact same cellular reprogramming as the mice. Their liver cells were switching into a stressed, survival-focused state. This reprogramming was detectable in patients with early-stage disease, long before any cancer appeared.

The strength of these early molecular warning signs in a patient’s biopsy was directly linked to their future risk. 

Patients whose liver tissue showed stronger ‘stress signatures’ were significantly more likely to be diagnosed with HCC up to 10 to 15 years later.

The researchers said: ‘Our data suggest that even early stress can precipitate cellular responses… which prime long-term tumorigenesis.’

Liver cancer, specifically the most common type, HCC, often develops silently, with few or no clear symptoms in its earliest and most treatable stages. However, as the disease progresses, warning signs begin to emerge.

These can include unexplained weight loss, a loss of appetite, or feeling unusually full after a small meal. Pain or discomfort may develop in the upper right abdomen, and jaundice, a yellowing of the skin and the whites of the eyes, can occur as the liver struggles to function.

Other signs are nausea, fatigue, easy bruising or bleeding and a swollen abdomen due to fluid buildup, known as ascites. These symptoms often appear only after the cancer is advanced.

Researchers said their findings underscore the vital importance of proactive monitoring for individuals with known risk factors, such as chronic fatty liver disease, hepatitis or cirrhosis.

Their study was published in the journal Cell.