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<p>Pancreatic α cell senses amino acid availability to adjust secretion function and proliferation, yet the underlying molecular mechanisms remain unclear. Here, α cell-specific deletion of CBP/p300 in mice leads to hypoglucagonemia and hyperaminoacidemia, along with decreased functional pancreatic α cell mass due to impaired cell proliferation, dedifferentiation, and cell loss. The knockout of CBP/p300 blocks glucagon receptor antibody-stimulated α cell proliferation and mTORC1 signaling in mice. In CBP/p300-deficient α cells, single-cell RNA sequencing reveals upregulated autophagy-related genes and downregulated α cell identity genes and amino acid transporters, including <i>Slc7a2</i>. <i>Slc7a2</i> is involved in regulating α cell identity gene expression through lysine-facilitated H3K27 acetylation. In addition, <i>Slc7a2</i> downregulation compromises arginine-stimulated mTORC1 signaling, thereby suppressing α cell proliferation and triggering autophagy. Collectively, our findings uncover CBP/p300 as central regulators of functional α cell mass partially by orchestrating Slc7a2-mediated amino acid sensing.</p>

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CBP/p300 is critical for the expansion and maintenance of functional pancreatic α cell mass

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月11日

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  • Shushu Wang,
  • Tianjiao Li,
  • Chunxiang Sheng,
  • Jialin Tan,
  • Yuling Yang,
  • Xiaoqin Ma,
  • Yun Liu,
  • Rui Wei,
  • Feiye Zhou,
  • Libin Zhou,
  • Xiao Wang

摘要

Pancreatic α cell senses amino acid availability to adjust secretion function and proliferation, yet the underlying molecular mechanisms remain unclear. Here, α cell-specific deletion of CBP/p300 in mice leads to hypoglucagonemia and hyperaminoacidemia, along with decreased functional pancreatic α cell mass due to impaired cell proliferation, dedifferentiation, and cell loss. The knockout of CBP/p300 blocks glucagon receptor antibody-stimulated α cell proliferation and mTORC1 signaling in mice. In CBP/p300-deficient α cells, single-cell RNA sequencing reveals upregulated autophagy-related genes and downregulated α cell identity genes and amino acid transporters, including Slc7a2. Slc7a2 is involved in regulating α cell identity gene expression through lysine-facilitated H3K27 acetylation. In addition, Slc7a2 downregulation compromises arginine-stimulated mTORC1 signaling, thereby suppressing α cell proliferation and triggering autophagy. Collectively, our findings uncover CBP/p300 as central regulators of functional α cell mass partially by orchestrating Slc7a2-mediated amino acid sensing.