Loss of Intestinal MSTN Promotes GLP-1 Secretion Through SGLT1 Palmitoylation.

Abstract

Intestinal glucagon-like peptide-1 (GLP-1) is secreted by intestinal L cells in a glucose-dependent manner. The localization and surface abundance of glucose-sensing proteins on the cell membrane affect the response to glucose, but the regulatory mechanism remains poorly understood. Here, we show that S-palmitoylation is required for stable plasma membrane enrichment of SGLT1 and for SGLT1-mediated GLP-1 secretion. Notably, myostatin (MSTN) was identified as a key upstream regulator of this modification. Intestinal MSTN deficiency markedly enhanced SGLT1 palmitoylation, increased its plasma membrane abundance, and thereby promoted glucose-stimulated GLP-1 secretion. Importantly, simvastatin induced intestinal MSTN upregulation and impaired glucose homeostasis, whereas MSTN deficiency largely alleviated these effects. Mechanistically, MSTN regulated the expression of the palmitoyl acyltransferase ZDHHC20, which catalyzed SGLT1 S-palmitoylation at Cys301. Blocking SGLT1 palmitoylation attenuated SGLT1 membrane enrichment and markedly suppressed the induction of GLP-1 secretion caused by MSTN deficiency. Collectively, our research results have revealed a new mechanism by which MSTN regulates intestinal endocrine function and S-palmitoylation modification promotes GLP-1 secretion, providing potential targets for regulating endogenous GLP-1 secretion in the intestine and treating metabolic diseases related to glucose imbalance.