Discovery of the path that causes fatty liver

A study published in the journal Nature Communications described a protein that is a key regulator of fatty liver disease in mice.

Nonalcoholic fatty liver disease (NAFLD) is a liver disease characterized by no history of excessive drinking, accumulation of fat in hepatocytes caused by various causes, and hepatic steatosis and lipid buildup. In the past few decades, the incidence of NAFLD has doubled and it has become the most common liver disease in Western countries.

Although NAFLD has little or no symptoms at the initial stage, it is a potentially serious disease that can progress to an inflammatory state called steatohepatitis (NASH), which can result in advanced liver fibrosis, cirrhosis, and liver failure, and liver tumors.

Despite the urgent medical needs, the FDA has not approved any drugs for NASH treatment so far. The current diagnosis of NASH relies on liver biopsy assessment, and the purpose of treatment is to control the progression of obesity, type II diabetes, and hyperlipidemia. Weight management is NASH's primary treatment option, which reduces liver enzyme levels, improves insulin sensitivity and liver histology, and delays disease progression. Therefore, the key to preventing and treating the disease is to better understand the development of the disease.

Researchers at the Karolinska Institute have shown that a protein called GPS2 (G protein pathway inhibitor 2) is a crucial regulator of lipid metabolism pathways in hepatocytes. Their results suggest that this mechanism may affect the development of disease in mice and humans.

To find out the functions and targets of GPS2 in hepatocytes, the researchers designed knockout mice that lack GPS2 only in hepatocytes (GPS2 is still present in other cell types) and then fed these mice with a special diet to induce NASH status. They found that GPS2 knockout mice did not develop into NASH, which is unexpected.

Next, the team discovered a previously unknown role for GPS2 in specifically inhibiting fatty acid receptors called PPARα by using sequencing-based techniques to elucidate GPS2-dependent changes in gene expression. They further verified the cooperative relationship between GPS2 and PPARα by extensive physiology and histological analysis of knockout mice.

The team worked with clinical researchers from Belgium and France to analyze gene expression data from liver biopsies from patients diagnosed with different stages of NAFLD. They found that GPS2 levels were significantly associated with characteristic gene expression of NASH in the disease stage.

This suggests that humans may also have a path of disease development similar to mice. The identified mechanism may help explain the susceptibility of individual patients to the more severe stages of fatty liver development.

The researchers believe that this new hepatocyte pathway may be related to future therapeutic strategies and that the GPS2 pathway in liver immune cells should be studied more deeply. At the same time, it is necessary to learn more about the additional GPS2 functions in other liver cell types.

Cite this article

CUSABIO team. Discovery of the path that causes fatty liver.


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