The protein that keeps the pancreas from digesting itself
Potential new therapeutic target for pancreatitis and pancreatic cancer
Date:
April 21, 2022
Source:
Salk Institute
Summary:
Scientists report that a protein known as estrogen-related receptor
gamma is critical for preventing pancreatic auto-digestion in
mice. Moreover, they discovered that people with pancreatitis have
lower levels of this protein in cells affected by this inflammation.
FULL STORY ========================================================================== Every day, your pancreas produces about one cup of digestive juices,
a mixture of molecules that can break down the food you eat. But if
these powerful molecules become activated before they make their way
to the gut, they can damage the pancreas itself -- digesting the very
cells that created them, leading to the painful inflammation known as pancreatitis, and predisposing a person to pancreatic cancer.
==========================================================================
Now, Salk scientists report in the journal Gastroenterology on April 21,
2022 that a protein known as estrogen-related receptor gamma (ERR ɣ)
is critical for preventing pancreatic auto-digestion in mice. Moreover,
they discovered that people with pancreatitis have lower levels of ERR
ɣ in cells affected by this inflammation.
These findings suggest that new therapies aimed at regulating ERR ɣ activity could help prevent or treat pancreatitis and pancreatic cancer.
"Our finding provides new insight into both the basic biology of how
pancreas cells function, and what might drive pancreatitis and pancreatic cancer," says Professor Ronald Evans, director of Salk's Gene Expression Laboratory, March of Dimes Chair in Molecular and Developmental Biology,
and co-senior author of the study.
The pancreas is home to two main cell types with distinct functions:
beta cells that release insulin to control blood sugar levels and acinar
cells that produce digestive juices. Evans and his colleagues previously discovered that ERR ɣ helps pancreatic beta cells release insulin
and might be useful as a treatment for diabetes. In follow-up studies,
the team also discovered that mice lacking ERR ɣ developed severe pancreatitis.
To understand the role of ERR ɣ in pancreatic acinar cells, the researchers compared mice, as well as isolated cells, with and without
the protein. They discovered ERR ɣ is required for the functioning
of the acinar cells' mitochondria -- organelles that generate energy.
========================================================================== "Mitochondria have been known to be the major source of energy in acinar
cells since the 1960s, but the factor that controls this vital energy production program in acinar cells has been a long-standing mystery,"
says co-senior author Jae Myoung Suh of the Korea Advanced Institute of
Science and Technology (KAIST), in South Korea.
Without ERR ɣ, acinar cells not only have dysregulated energy
regulation but, as a result, incorrectly activate digestive enzymes to
start auto- digestion.
"The mitochondria in these cells have to be particularly robust," says
Staff Scientist Michael Downes, a co-author of the new work. "If things go wrong, those digestive enzymes are activated and then auto-digestion of
the pancreas begins." The group showed that not only did auto-digestion
of pancreatic acinar cells begin in the absence of ERR ɣ, but so
did cellular changes that indicate early pancreatic cancer.
The researchers next turned to data from patients with pancreatitis
to determine whether the mouse and lab results are relevant to human
disease. They compared pancreatitis biopsies with those collected from
normal pancreatic cells -- including healthy sections of the pancreas
in the same patients. Cells affected by pancreatitis, they discovered,
had lower levels of ERR ɣ.
==========================================================================
"We examined data across multiple different locations and patient
groups and found that ERR ɣ is very consistently decreasing with pancreatitis," says co-first author Tae Gyu Oh, a bioinformatics analyst
at Salk.
Oh and his colleagues went on to show that levels of 83 other genes,
many of which are directly regulated by ERR ɣ, were also altered
in the pancreatitis samples. Moreover, when they searched through the
data from two large studies comparing gene expression in people, they discovered that some of those 83 genes are associated with rare types
of inherited pancreatitis and pancreatic cancer.
"The fact that this was linked back to patients with chronic pancreatitis suggests that ERR ɣ is clinically relevant and could make a good
drug target in the future," says Evans.
The researchers are planning future studies to look in depth at the pre- cancerous changes that ERR ɣ dysregulation and pancreatitis lead to,
as well as how drugs could help increase ERR ɣ to prevent or treat pancreatic diseases.
Other authors include Weiwei Fan, Sagar P. Bapat, Ye Zheng, Ruth
T. Yu, Annette Atkins and Eiji Yoshihara of Salk; Jinhyuk Choi,
Heewon Jung, Kun-Young Park, Hyemi Shin, Taehee Jo, Du-Seock Kang,
Sujung Hong, and Pilhan Kim of KAIST; Dipanjan Chanda and In-Kyu Lee
of Kyungpook National University Hospital; Jina Kim and Sung Jin Cho of Daegu-Gyeongbuk Medical Innovation Foundation; Moongi Ji and Man-Jeong
Paik of Sunchon National University; Minkyo Jung and Ji Young Mun of
Korea Brain Research Institute; Takashi Syoji of Kyoto University;
Ayami Matsushima of Kyushu University; David C. Whitcomb, Phil Greer
and Brandon Blobner of the University of Pittsburgh; Mark O. Goodarzi
and Stephen J. Pandol of Cedars-Sinai Medical Center; Jerome I. Rotter
of UCLA; Christopher Liddle of the University of Sydney; as well as the
entire North American Pancreatitis Study 2 (NAPS2) Consortium.
The work was supported in part by the National Institute of Diabetes
and Digestive and Kidney Diseases (T32 DK063922-17, NIH DK061451 and R01DK120480), National Center for Research Resources (UL1 RR024153 and UL1TR000005), NIH R
========================================================================== Story Source: Materials provided by Salk_Institute. Note: Content may
be edited for style and length.
========================================================================== Journal Reference:
1. Jinhyuk Choi, Tae Gyu Oh, Heewon Jung, Kun-Young Park, Hyemi
Shin, Taehee
Jo, Du-Seock Kang, Dipanjan Chanda, Sujung Hong, Jina Kim, Hayoung
Hwang, Moongi Ji, Minkyo Jung, Takashihoji, Ayami Matsushima,
Pilhan Kim, Ji Young Mun, Man-Jeong Paik, Sung Jin Cho, In-Kyu Lee,
David C. Whitcomb, Phil Greer, Brandon Blobner, Mark O. Goodarzi,
Stephen J. Pandol, Jerome I. Rotter, Weiwei Fan, Sagar P. Bapat,
Ye Zheng, Chris Liddle, Ruth T.
Yu, Annette R. Atkins, Michael Downes, Eiji Yoshihara, Ronald
M. Evans, Jae Myoung Suh. Estrogen-Related Receptor g maintains
pancreatic acinar cell function and identity by regulating cellular
metabolism.
Gastroenterology, 2022; DOI: 10.1053/j.gastro.2022.04.013 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/04/220421100132.htm
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