Non-alcoholic
fatty liver disease (NAFLD) is an important risk factor for type 2
diabetes and cardiovascular diseases. In a Perspective in Cell Metabolism,
the researchers first highlight the dysregulation of hepatokines –
proteins released from the liver – in people with NAFLD. Then, they
discuss pathomechanisms of type 2 diabetes and cardiovascular diseases
specifically related to NAFLD by focusing on hepatokine-related organ
crosstalk. Finally, they propose how the determination of major
hepatokines and adipokines (proteins released from fat) can be used for
the identification of subtypes of people with NAFLD, to better implement
precision medicine in clinical practice.
Worldwide
more than 25% of adults and 3-10% of children have NAFLD. The
percentage of NAFLD is much higher when obesity and/or diabetes is
present in adults (60%) and in children (⁓40%).
These numbers are alarming, because NAFLD, and more so non-alcoholic
steatohepatitis, is the main cause of chronic liver disease and liver
cancer. Furthermore, results from large studies reveal that NAFLD
associates with ⁓2.5-fold increased risk of type 2 diabetes and ⁓1.5-fold
increased risk of cardiovascular events. But what are the mechanisms by
which the fatty liver impacts on the genesis of type 2 diabetes and
cardiovascular diseases? Furthermore, how can the impact of fatty liver
be separated from the impact of increased abdominal obesity, which is
often found in people with fatty liver, on these diseases?
The
researchers have been studying these questions since many years. They
have identified important hepatokines that are dysregulated in NAFLD and
have described their role in metabolism.
‘We
found that the hepatokine fetuin-A is increasingly produced by the
fatty liver and that it strongly predicts the incidence of type 2
diabetes and cardiovascular events. We also identified mechanisms of
cellular action of fetuin-A to promote insulin resistance, subclinical
inflammation and impairment of insulin secretion’, highlights the author
and adds: ‘We identified another important hepatokine which is
increasingly produced by the fatty liver – follistatin.
We found mechanisms up-regulating the production of follistatin in the
liver and identified the mechanisms by which follistatin increases
glucose levels and insulin resistance. In large human cohorts we found
that follistatin associates with an increased risk of type 2 diabetes’.
In
their present article the researchers describe the mechanisms of action
of these hepatokines and summarize knowledge about other hepatokines
that are being studied in the scientific community.
Finally,
the researchers made use of a currently very popular research tool –
cluster analysis, a data dimensionality reduction approach – to
disentangle the close relationship between fatty liver and abdominal
obesity and to identify subtypes of people with fatty liver.
Clustering
the parameters liver fat content, visceral fat mass, the hepatokine
fetuin-A and the adipokine adiponectin, they identified 3 clusters. The
clusters 1 and 3 had similar insulin resistance and elevated liver fat
content but largely differed in the plasma levels of fetuin-A and
adiponectin.
The
researchers concluded that they identified subtypes of people with
fatty liver having different pathomechanisms of insulin resistance and
that the research into hepatokines may be helpful to find other subtypes
of fatty liver in the future.
https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00006-2
http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fthe-role-of-hepatokines&filter=22