Biologists find new protective factor against excessive lipid
accumulation in liver of obese mouse

Date:
April 19, 2022
Source:
The University of Hong Kong
Summary:
Non-alcoholic fatty liver disease (NAFLD), commonly known as fatty
liver disease, is a prevalent disease frequently seen in obese
people. Having high fat content in the liver is detrimental as it
is strongly associated with severe health problems like diabetes,
high blood pressure, and liver cancer. A research team uncovers
a new protective mechanism against this disorder.



FULL STORY ========================================================================== Non-alcoholic fatty liver disease (NAFLD), commonly known as fatty liver disease, is a prevalent disease frequently seen in obese people. Having
high fat content in the liver is detrimental as it is strongly associated
with severe health problems like diabetes, high blood pressure, and liver cancer. A research team led by Dr Chi Bun CHAN, Assistant Professor from
the School of Biological Sciences, Faculty of Science, the University
of Hong Kong (HKU), uncovers a new protective mechanism against this
disorder. The research findings have recently been published in the
scientific journal Hepatology.


==========================================================================
The liver is the vital organ that orchestrates the overall glucose and
fat metabolisms in the human body. Disruption of the fat metabolism in
the liver will eventually result in hyperglycemia and hyperlipidemia,
which are strong risk factors for developing diabetes, hyperlipidemia,
and liver cancer. It is predicted that the number of NAFLD patient
will increase from 80 million in 2015 to 100 million in 2030. While the outcomes of fat accumulation in the liver have been well established,
it remains unclear if the liver possesses any defensive mechanism to
work against the damage.

To answer this question, Dr Chan's team examined the expression of genes
in the liver of high fat diet-induced obese mouse and found a protein,
SH3 domain binding kinase (SBK1), was exclusively elevated in the
obese mouse liver. SBK1 is a protein kinase first discovered in 2001,
but no follow-up study has been performed to determine its functions in mammals. Hence, the functions of this novel protein remain unknown.

For the first time, Dr Chan's team found that fatty acid accumulation is
an inducer of SBK1 in the mouse liver. They also observed that the mice
without the SBK1 gene in their liver, called 'LSKO (liver-specific SBK1 knockout)' mice, have higher lipid accumulation and fibrosis in this
tissue. Moreover, the LSKO mice displayed uncontrolled hepatic glucose
output and higher blood glucose level, and are less sensitive to insulin stimulation than their control cohort, which are strong indicators of
diabetes development.

In addition to the animal studies, Dr Chan's team also utilised cultured
cell models to answer how SBK1 gene controlled the lipid metabolism in
the liver.

They found that SBK1 phosphorylated and enhanced the activity of Nur77,
a well- established transcriptional factor, in liver cells to control
fatty acid uptake and lipid synthesis. When the SBK1 protein activity
was abolished in the liver cells, they took up more fatty acids and
developed excessive lipid accumulation that interfered the insulin
signaling. Surprisingly, another metabolic hormone in the liver cells, fibroblast growth factor 21 (FGF21), was also reduced when the SBK1
protein was abolished in the cultured liver cells and the LSKO mice.

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

To extend their findings to therapeutic application, the research team
further tested if manipulating the SBK1 protein activity 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 mouse's liver with fructose diet-induced fatty liver disease
and found pathological symptoms like liver steatosis, inflammation,
etc. hyperlipidemia, and hyperglycemia were all alleviated.



==========================================================================
'Our findings clearly show that SBK1 protein is an important regulator of
the lipid metabolism that was neglected before,' said Dr Chan. 'We are
very excited to see that increasing its activity effectively alleviates
the health problems caused by fatty liver. But we still need more
studies to fully depict its functional activity so that we can develop
SBK1 activator as a new treatment agent for this common liver disease,'
Dr Chan further added.

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

Key findings on the liver protective factor SBK1:
* Fatty acid accumulation will induce SBK1 protein in the mouse liver,
which serves to control lipid accumulation and fibrosis in the
liver.

* SBK1 protein phosphorylates and enhances the activity of Nur77,
a well-
established transcriptional factor, in liver cells to control the
expression of genes for lipid synthesis. If the activity of SBK1 is
inhibited, the Nur77-controlled gene expression will be interfered,
leading to more fatty acid uptake and lipid accumulation.

* Insufficient SBK1 protein decreases the production of a metabolic
hormone
fibroblast growth factor 21 (FGF21) in the liver cell, which
impairs the communication between the liver and other organs,
leading to the development of insulin resistance in other tissues.

Note: SBK1 protein -- serves to control lipid accumulation in the liver.

Nur77 -- a well-established transcriptional factor in liver cells to
control the expression of genes for lipid synthesis.

FGF21 -- a metabolic hormone fibroblast growth factor 21 in the liver
cell, which impairs the communication between the liver and other organs.


========================================================================== Story Source: Materials provided by The_University_of_Hong_Kong. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Palak Ahuja, Xinyi Bi, Chun Fai Ng, Margaret Chui Ling Tse,
Miaojia Hang,
Brian Pak Shing Pang, Elsie Chit Yu Iu, Wing Suen Chan, Xin Ci
Ooi, Anqi Sun, Oana Herlea‐Pana, Zhixue Liu, Xiuying Yang,
Baowei Jiao, Xin Ma, Kelvin Ka Lok Wu, Leo Tsz On Lee, Kenneth
King Yip Cheng, Chi Wai Lee, Chi Bun Chan. Src homology 3 domain
binding kinase 1 protects against hepatic steatosis and insulin
resistance through the Nur77‐ fibroblast growth factor 21
pathway. Hepatology, 2022; DOI: 10.1002/ hep.32501 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220419103243.htm

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