【Science】Fatty liver "son preference"? Rooted in the evolutionary trade-off between immunity and metabolism

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Written by Lily

It is well known that there are sex-specific differences
in the incidence of many diseases.
It is also well known that certain genes associated with metabolic or other diseases are selected for retention during evolution – because these genes can adapt to other conditions
。 A recent study linked the two concepts together: the team used mouse models to show that the liver transcription factor BCL6 plays a key role in determining genetic program activity in male and female mice, and thus the survival rate of the mice under different conditions (see the Perspective by Waxman and Kineman); Male mice have high expression of BCL6 and are therefore protected from infection, but are susceptible to metabolic diseases — the opposite was
observed in magnetic mice.

On October 20, researchers from the University of California, San Francisco published a paper
in the journal Science entitled "An evolutionary trade-off between host immunity and metabolism drives fatty liver in male mice.
" 。 The study showed that the liver transcription factor BCL6 played a role in promoting the phenotype that male mice were more likely to develop non-alcoholic fatty liver disease.
But in the case of bacterial infection, BCL6 can improve survival in male mice — one of
the results of evolutionary trade-off.

style="box-sizing: border-box;" _msthash="251139" _msttexthash="1018732">Sex ditypism of liver gene expression

 01 

The transcription factor STAT5B regulates sexual dimorphic in liver gene expression
.
STAT5B can be activated by growth hormone: in the male liver, its DNA-binding activity is only intermittently activated; In the magnetic liver, its DNA-binding activity is continuously activated
.
By regulating the expression levels of male-specific BCL6 and female-specific CUX2, STAT5B enhanced the hepatic sex-specific phenotype from transcriptional and epigenetic
perspectives.
For male livers, BCL6 competes with female-specific genes
at the STAT5B binding site on the chromosome of liver cells.
The transcriptional activator PPARa has the effect of inhibiting the oxidation of liver esters and promoting fatty liver - in this way, the functions of PPARa and BCL6 can be considered relative
.

METTL14 is another regulator of gender dityping, and BCL6 inhibits METTL14
in the male liver in the case of excessive fat intake.
By modifying the N6 adenosine (m6A) associated with adipose synthesis genes, METTL14 regulates hepatic triglyceride levels, which protects the RNA from degradation and thus inhibits fat synthesis
.
It can be seen that in the pathogenesis of diet-induced nonalcoholic fatty liver, the liver transcription factor BCL6 is one of
the key factors that males are more inclined to develop.

The key role of BCL6 in the evolutionary trade-off

 02 

This study found that BCL6 plays a very important role
in the evolutionary trade-off.
Due to the antagonism of growth hormone stimulation and DNA-bound STAT5B activity, the expression level of BCL6 in liver cells in female mice was relatively low.
Therefore, the sex factor of female mice protects the risk of
high-fat food-induced non-alcoholic fatty liver disease in female mice.
However, it is worth noting that low BCL6 expression levels increase the risk of death after bacterial infection—in the sepsis model (induced by intravenous E.
coli), female mice have higher mortality; In contrast, BCL6 is expressed at high levels in the liver of male mice, making male mice more susceptible to non-alcoholic fatty liver disease, but reducing the mortality rate
after E.
coli infection.
The research team further confirmed these results
with a male mouse model with specific deletion of BCL6 in liver cells.

In the sepsis model, lipoprotein levels and circulatory esters are directly associated
with disease severity.
The team also confirmed that the BCL6 signaling pathway mediates sex differences in sepsis—specifically, BCL6 inhibits APOC3 levels in the cytoplasm (APOC3 inhibits triglyceride clearance).

In addition, the researchers also found that high levels of triglycerides are one of the important reasons for the high mortality rate of sepsis, and BCL6 and APOC3 may become promising clinical targets for sepsis
.

The study also found that a suitable environment (ambient temperature around 30 degrees Celsius) often leads to sex differences
in fatty liver and sepsis.
In this suitable environment, mice do not need to burn fat to maintain body temperature, and the relevant models are more likely to mimic human immunological function and obesity-related metabolic diseases
.
Compared to males, female mice and humans have a stronger immune response to infection, but also have a higher lethality rate — an indication of evolutionary
trade-offs.

Research implications

 03

In this study, for the first time, the researchers linked liver ester metabolism to bacterial infection response through sex differences, and took sex as a key biological variable when building relevant animal models, thereby more realistically simulating human disease
.
It is worth mentioning that when referring to sex differences, in addition to the genetic background and the direct influence of sex hormones, the regulatory networks downstream of hormones need to be taken into account, because these networks are generally more relevant
to disease.

Adaptation to infection and dietary stress determines mammalian physiology and disease risk – and how this adaptation affects sexual bias disease is still understudied
.
This study shows that sex-dependent liver gene programming provides a strong (approximately 300%) survival advantage
for male mice during a lethal bacterial infection.
Transcription factor B-cell lymphoma 6 (BCL6), gene expression in the masculine liver during adolescence, is critical
for this advantage.
However, the protection of the BCL6 protein comes at a cost in case of dietary overdose, which leads to significant fatty liver and glucose intolerance
in men.
Deletion of liver BCL6 can reverse these phenotypes but significantly reduce male survival during infection, establishing a sex-dependent trade-off
between host defenses and metabolic systems.
These findings strongly demonstrate that some of today's sex-biased diseases are rooted in the age-old evolutionary trade-off
between immunity and metabolism.

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style="white-space: normal;box-sizing: border-box;">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
.