Under a high-fat diet: normal liver cells become the "look" of a tumor...

Hepatocellular carcinoma (HCC) is a high-mortality malignant tumor originating from normal liver cells, accounting for 90% of primary liver cancer, and ranking third in the global cancer-related death list.

Obesity, smoking and diabetes are known to be the main risk factors for liver cancer.

Today, the incidence of obesity and liver cancer has increased year by year.

Therefore, understanding how excess fat leads to liver cancer is essential for identifying the pathogenesis and finding effective treatments.

Recently, in a new study published in "Cancer Research", a research team from the VIB-KU Leuven Cancer Biology Center in Belgium found that when exposed to a high-fat diet, normal untransformed liver cells undergo metabolism.
This fat-induced change is similar to the metabolic state of aggressive liver cancer cells.

In short, when the liver is exposed to excess fat, normal liver tissue is more likely to become cancerous.

This discovery directly connects diet, obesity and the occurrence of liver cancer.

The effective utilization of tissue environment and nutrients are important regulators of cellular processes.

Many cancer-related studies have shown that, compared with primary tumors, the effective utilization of nutrients can directly regulate cell metabolism by defining metabolic dependency, metabolic heterogeneity within the tumor, and metastatic components.

These studies emphasize the importance of studying cell metabolism in the context of increasing nutrient supply.

In this study, the research team studied normal tissue metabolism under disease conditions and compared the metabolism between different tissues.

By comparison, they observed a signal-independent metabolic link of nutrient availability.

First, the researchers tested the metabolic changes in the liver tissue of mice fed a high-fat diet at the early stage when no tumors appeared and at the late stage of tumor formation.

They found that before there was any clue that cancer was developing, liver cells used glucose in the same way as tumors.

This way of consuming a lot of glucose is one of the well-known characteristics of cancer, the "Warburg effect".

Subsequently, the researchers studied what happens when the tumor is fully formed and measured the sensitivity of the mice to glucose.

Professor Sarah-Maria Fendt, the corresponding author of the study and the Cell Metabolism and Metabolic Regulation Laboratory of the VIB-KU Leuven Cancer Biology Center: “It is surprising that despite diabetes, cancerous mice fed a high-fat diet can resemble Healthy mice consume glucose in the blood as easily.

"It is well known that too much fat is the main cause of insulin resistance, which inhibits insulin signaling in the liver and skeletal muscle.

Insulin resistance can also reduce glucose uptake in the liver and skeletal muscle and increase liver gluconeogenesis.

The important thing is that fat can directly change the metabolism of non-transformed cells in the liver.

Using the most advanced glucose-13C6 tracking technology, researchers observed how glucose molecules are used in cells and tissues.

They found that regardless of whether the mice were fed a high-fat diet or a normal diet, the tumor tissue would break down glucose in a consistent manner.

These findings indicate that when normal liver cells transform into cancer cells, their metabolism will continue to increase glucose consumption.

Since high-fat diets can cause these changes before cancer, this may mean that non-cancer liver tissues are more likely to become cancerous under high-fat diets.

Mice fed a high-fat diet showed increased production of lactic acid when stimulated by glucose.

Subsequently, the team tested whether this similar change would occur in the human body.

They tested the metabolic response of 20 healthy volunteers after taking glucose pills and observed a correlation between waist circumference and lactic acid production.

The research team also studied the underlying mechanism of this effect.

They found that before any cancer develops, liver tissue exposed to high fat seems to use another fat metabolism pathway in a cell compartment called peroxisomes.

Using liver cancer cells, the researchers confirmed that peroxisome metabolism increases cellular stress and glucose uptake.

This study confirmed that a high-fat diet can promote the formation of liver cancer in mice, and that regardless of the diet background, the glucose metabolism changes of all mouse tumors are similar to those of non-transformed mouse livers exposed to fat.

This means that fat can induce glucose-mediated metabolic changes in non-transformed liver cells, and this change is exactly similar to the metabolic changes found in hepatocellular carcinoma.

Paper link: https://cancerres.
aacrjournals.
org/content/early/2021/03/04/0008-5472.
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