Researchers discover new protective mechanism against non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD), commonly known as fatty liver disease, is a common disease frequently seen in obese people. Having a high fat content in the liver is detrimental as it is strongly associated with serious health issues like diabetes, high blood pressure, and liver cancer.

A research team led by Dr. Chi Bun CHAN, assistant professor at the School of Biological Sciences of the Faculty of Science of the University of Hong Kong (HKU), discovers a new mechanism of protection against this disorder. The research results were recently published in the world-renowned scientific journal Hepatology.

The liver is the vital organ that orchestrates the overall glucose and fat metabolisms in the human body. Disturbance of fat metabolism in the liver will eventually lead to hyperglycemia and hyperlipidemia, which are important risk factors for the development of diabetes, hyperlipidemia and liver cancer. It is expected that the number of NAFLD patients will increase from 80 million in 2015 to 100 million in 2030. has a defense mechanism to act against damage.

To answer this question, Dr. Chan’s team examined gene expression in the liver of obese mice induced by a high-fat diet and found that a protein, SH3 domain-binding kinase (SBK1) , was exclusively elevated in the liver of obese mice. SBK1 is a protein kinase first discovered in 2001, but no follow-up studies have been done to determine its functions in mammals. Therefore, the functions of this new protein remain unknown.

Three search keywords:
SBK1 protein – serves to control the accumulation of lipids in the liver.
Nur77 – a well-established transcriptional factor in liver cells to control gene expression for lipid synthesis.
FGF21 – a metabolic hormone fibroblast growth factor 21 in the liver cell, which impairs communication between the liver and other organs.

For the first time, Dr. Chan’s team discovered that fatty acid accumulation is an inducer of SBK1 in mouse liver. They also observed that mice lacking the SBK1 gene in their liver, called “LSKO (liver-specific SBK1 knockout) mice”, show higher lipid accumulation and fibrosis in this tissue. Moreover, LSKO mice displayed uncontrolled hepatic glucose production and higher blood sugar, and are less responsive to insulin stimulation than their control cohort, which are good indicators of the development of diabetes.

In addition to animal studies, Dr. Chan’s team also used cultured cell models to determine how the SBK1 gene controls lipid metabolism in the liver. They found that SBK1 phosphorylates and increases the activity of Nur77, a well-established transcription factor, in liver cells to control fatty acid uptake and lipid synthesis.

When SBK1 protein activity was abolished in liver cells, they absorbed more fatty acids and developed excess lipid accumulation that interfered with insulin signaling. Surprisingly, another metabolic hormone in liver cells, fibroblast growth factor 21 (FGF21), was also reduced when the SBK1 protein was abolished in cultured liver cells and LSKO mice.

Since FGF21 is an important hormone of the liver to communicate with other peripheral organs like white adipose tissue, the reduced production of FGF21 hormone in the LSKO liver thus impairs the communication between the liver and other organs, resulting in the development of insulin resistance in other tissues. .

To extend their findings to therapeutic application, the research team then tested whether manipulating the activity of the SBK1 protein in the liver could rescue the damaging effect of obesity. Using adenovirus-mediated gene delivery, they transiently increased the amount of SBK1 protein in the liver of mice with fructose diet-induced fatty liver disease and found pathological symptoms like fatty liver disease. , inflammation, etc. hyperlipidemia and hyperglycemia were all alleviated.

“Our findings clearly show that the SBK1 protein is an important regulator of lipid metabolism that was previously overlooked,” Dr. Chan said. “We are very happy to see that the increase in its activity effectively alleviates the health problems caused by fatty liver disease. But we still need more studies to fully describe its functional activity so that we can develop the SBK1 activator as a novel treatment agent for this common liver disease,” added Dr. Chan.

This work was supported by the Hong Kong Research Grant Council, the Health and Medical Research Fund and the HKU Seed Fund for Basic Research.

Key findings on liver protection factor SBK1:

  • Accumulation of fatty acids will induce SBK1 protein in mouse liver, which serves to control lipid accumulation and fibrosis in the liver.
  • The SBK1 protein phosphorylates and enhances the activity of Nur77, a well-established transcription factor, in liver cells to control gene expression for lipid synthesis. If the activity of SBK1 is inhibited, the expression of the gene controlled by Nur77 will be interfered with, leading to greater uptake of fatty acids and accumulation of lipids.
  • Insufficient amount of SBK1 protein decreases the production of a metabolic hormone, fibroblast growth factor 21 (FGF21) in the liver cell, which impairs communication between the liver and other organs, leading to the development of resistance insulin in other tissues.

Source:

Journal reference:

Ahuja, P. et al. (2022) Src homology domain 3-binding kinase 1 protects against fatty liver disease and insulin resistance through the Nur77-fibroblast growth factor 21 pathway. Hepatology. doi.org/10.1002/hep.32501

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