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Gene expression of non-apoptotic pancreatic acinar cell death with autophagy

ABSTRACT: Serine protease inhibitor Kazal type 3 (Spink3) is a trypsin inhibitor in the pancreas. Spink3-/- pancreatic acinar cells are dead with excessive autophagy at birth (p0.5). To prove the role of nonapoptotic cell death with autophagy, we generated by transgenic technology the pancreas of Spink3-/-;XKI/+ mice contained both normal and dying acinar cells with autophagy. In this new mouse model, chronic inflammation occurred in the pancreas, indicating that some signals from nonapoptotic dead cell induce chronic inflammation in the pancreas.

ORGANISM(S): Mus musculus

PROVIDER: GSE48946 | GEO | 2016/07/16

SECONDARY ACCESSION(S): PRJNA212376

REPOSITORIES: GEO

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Project description:Pancreas volume or mass varies more than 3-fold among adult humans. The heterogeneity is likely the result of genetics, diseases, and nutrition. Dietary protein intake and blood amino acid levels are known to affect pancreas mass, but the underlying mechanism is not well understood. The goal of this study is to determine how increased blood amino acid level (hyperaminoacidemia) induces pancreas expansion.Multiple complementary mouse and zebrafish models were used to study the impact of hyperaminoacidemia on pancreatic mass, acinar cell size and proliferation. Blood amino acid levels were manipulated by dietary protein content, or by pharmacologic or genetic interruption of glucagon signaling (IGS). The activation of mammalian target of rapamycin complex 1 (mTORC1) and Yes-associated protein 1 (YAP) were determined by pS6 and YAP staining. Sirolimus administration in mice and knockdown of solute carrier family 38 member 5b (slc38a5b) and yap/taz in zebrafish were used to determine the role of mTORC1, SLC38A5 and YAP/TAZ in acinar cell proliferation and pancreas expansion. We found that the IGS-induced pancreas expansion was the result of acinar cell proliferation and hypertrophy. Hyperaminoacidemia was the likely mediator as pancreas expansion was blunted by a low protein diet in mice and by knocking down the most highly expressed amino acid transporter gene, slc38a5b, in zebrafish lacking both glucagon receptor genes (gcgr-/-). In GCGR-Ab treated mice, inhibition of mTORC1 attenuated both hyperplasia and hypertrophy of acinar cells. There was a gene expression signature of YAP activation in acinar cells, consistent with increased YAP-expressing acinar cells in GCGR-Ab treated mice and increased fraction of acinar cells with nuclear YAP1 in gcgr-/- zebrafish. Knocking down yap1 or taz decreased mTORC1 activity and acinar cell hyperplasia and hypertrophy in gcgr-/- zebrafish. Hyperaminoacidemia leads to acinar cell proliferation and hypertrophy via activation of both mTORC1 and YAP pathways. The study discovered a previously unrecognized role of the YAP/Taz pathway in hyperaminoacidemia-induced acinar cell hypertrophy and hyperplasia.

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Gene expression of non-apoptotic pancreatic acinar cell death with autophagy

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