Sci Adv:BNIP3 is involved in lipid metabolism and can reduce the risk of liver cancer

Alcohol consumption and hepatitis C virus infection are known risk factors
for hepatocellular carcinoma, the most common form of liver cancer.
In addition, obesity-related nonalcoholic fatty liver disease has become a major contributing factor
to hepatocellular carcinoma in Western societies.
The underlying mechanism of obesity-induced liver cancer is unclear
.

A new study by researchers at the University of Chicago, "Lipid droplet turnover at the lysosome inhibits growth of hepatocellular carcinoma in a BNIP3-dependent manner," published in the journal Science Advances, shows that in a mouse model, BNIP3 The loss of protein leads to a decrease in the turnover of mitochondria and lipid droplets, which leads to the development of fatty liver and eventually liver cancer
.
In human liver cancer, studies have also shown that loss of BNIP3 expression is associated
with increased lipids and a poorer prognosis.

Research background

Obesity-related fatty liver disease, including nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, has become the leading cause
of hepatocellular carcinoma (HCC) in Western societies.
Obese patients have a higher relative risk of dying from HCC (1.
5 to 4-fold) than any other human cancer
compared with non-obese individuals.
Given the continuing rise in obesity rates in the U.
S.
population, efforts to understand how fatty liver contributes to HCC could be highly impactful
in identifying biomarkers that predict disease onset or progression, in addition to finding new therapeutic targets.

Altered mitochondrial function has been reported in human NAFLD and may lead to altered
lipid metabolism in a variety of ways.
"My lab is interested in
mitochondria and mitochondrial conversion in normal physiological environments and cancer.
Dr Kay Macleod said: "We studied a protein called BNIP3, which functions
as a mitochondrial cargo receptor.
Typically, this protein is significantly upregulated in the liver after fasting in mice, and it plays a role in protecting the liver from fat accumulation; However, eliminating this protein can lead to fatty liver
.
We therefore investigated further to understand how the underlying mechanism of loss of BNIP3 leads to lipid accumulation
in normal liver and liver cancer.
”

Research progress

To understand BNIP3's involvement in preventing lipid accumulation and fatty liver conditions, the researchers used chemocarcinogens to induce liver cancer in two groups of mice, one with BNIP3 intact and the other with BNIP3 deletion
.
It was then observed that in mice with BNIP3 deficiency, tumors developed earlier and grew faster
.
In addition, these tumors were filled with fat, whereas the tumors of BNIP3 intact mice were smaller and had no lipids
.
When these tumors were tracked over time, BNIP3 intact mice also exhibited lipid accumulation
similar to BNIP3-deficient mice.
More interestingly, BNIP3 has been silenced, suggesting a loss of
BNIP3 in liver cancer as the disease progresses.

These findings are consistent with human liver cancer patient data, which report a better
prognosis in patients with BNIP3 and less lipids in their tumors compared with patients with very high expression of genes associated with lipid synthesis.
The data again suggest that BNIP3 can inhibit tumorigenesis
in hepatocellular carcinoma by preventing lipid accumulation.
So the next question is how does BNIP3 regulate lipids?

When BNIP3 is reintroduced into hepatocellular cancer cells lacking BNIP3 using lentivirus, tumor cells stop accumulating lipids and they do not proliferate or grow as fast as cells
lacking BNIP3.
The researchers showed that this is due to BNIP3 causing lipid-to-mitochondrial switching
during a degradation cell they call "mitochondrial autophagy.
"

Next, the research team wanted to know how reducing lipid droplet turnover could prevent hepatocellular carcinoma
.
Lipid droplets store a variety of lipids
used to make cell membranes.
If a cell is growing or multiplying, it needs more membranes
.
BNIP3 will limit the amount of phospholipids in cells, thereby limiting the lipids
needed for new cell production.

"BNIP3 can both prevent tumors from developing and limit their progression
by preventing tumors that have already formed from growing faster or becoming more aggressive," Macleod said.
”

Research implications

The study suggests that to truly form hepatocellular carcinoma, it is necessary to get rid of BNIP3
.
This means that if there is a way to somehow stop BNIP3 from being silenced, this may limit the growth of liver tumors or prevent fatty liver in
the first place.
"I think the most exciting thing is that BNIP3 doesn't just promote mitochondrial renewal
," Macleod says.
By facilitating mitochondrial interaction and function, it actually regulates other organelles
in the cell.
”

Much attention has been paid
to tumor metabolism and how to target this process in cancer.
Most of them tend to focus on amino acid and glucose metabolism rather than lipid biology
.
Learning more about how lipid metabolism is dysregulated in cancer has not been studied in depth
.
The researchers' future work focuses on understanding how BNIP3 is regulated
in disease conditions and age.
At the same time, they are interested
in many other genes that play an important role in coping with nutritional stress.

Resources:

https://medicalxpress.
com/news/2022-10-mitochondria-lipid-turnover-liver-cancer.
html

_msthash="320090" _msttexthash="19521346">Note: This article is intended to introduce the progress of medical research and cannot be used as a reference
for treatment options.
If you need health guidance, please go to a regular hospital
.