Hepatic Protein disulfide isomerase A5 (PDIA5) improves hyperglycaemia and insulin resistance through stabilisation of ATF6
Authors' conclusion
Our findings identify a novel PDIA5-SYVN1-ATF6 regulatory axis that is crucial for maintaining hepatic glucose homeostasis. These results establish PDIA5 as a critical molecular checkpoint linking hepatic lipid overload to glucose dysregulation
Study context
- Population
- Liver biopsies from individuals with MASLD; mouse models of T2D; High-fat diet (HFD)-fed male mice, mouse primary hepatocytes, HEK293T cells; Pdia5 knockout male and liver-specific Pdia5-deficient female mice
Methodological detailshuman liver biopsies, mouse models, adenoviral-mediated hepatic overexpression, whole-body and liver-specific Pdia5 knockout
- Human liver biopsies
- Mouse models
- Adenoviral-mediated hepatic overexpression
- Whole-body and liver-specific Pdia5 knockout
Main finding
As reported in the abstract
- Hepatic PDIA5 expression significantly reduced in individuals with MASLD and diabetic mice
- Hepatic PDIA5 overexpression in HFD-fed mice ameliorated hyperglycaemia and improved glucose homeostasis by suppressing gluconeogenic genes (Pck1, G6pc1) and glucose production
- PDIA5 physically interacts with and stabilises ATF6, shielding it from SYVN1-mediated ubiquitination and proteasomal degradation
- ATF6 stabilisation attenuated CRTC2 recruitment to gluconeogenic promoters and suppressed PERK-TRB3 signalling, enhancing hepatic insulin sensitivity
- ATF6 knockdown abolished the protective effects of PDIA5 on glucose metabolism
- Genetic deletion of Pdia5 exacerbated glucose intolerance in HFD-fed mice
Original publication
Hepatic PDIA5 improves hyperglycaemia and insulin resistance through stabilisation of ATF6. Diabetologia. Published 17 September 2026. doi:10.
Composed by AI from the published abstract and checked against it. How Briefs are made →