Blunted Sirt1 Cleavage Lowers Circulating GIP and SREBP1 Activity, Curbing Intake and Hepatosteatosis with Age

ABSTRACT: SIRT1, an NAD⁺-dependent deacetylase, regulates health span and aging, yet is subjected to C-terminal (CT) cleavage by cathepsin B under stress,leading to its inactivation. To investigate the functional impact of this process, we generated a partial genetic ablation of the unstructured CT domain (ΔSirt1) and confirmed resistance to cathepsin B- mediated cleavage. ΔSirt1 mice maintained SIRT1 deacetylase activity with age and exhibited reduced body weight gain, primarily due to decreased bone length and liver weight. At 16 months of age, ΔSirt1 mice showed reduced food intake, which was associated with lower circulating levels of gastric inhibitory polypeptide (GIP) with age. Pharmacological inhibition of SIRT1 using EX527 increased both caloric intake and circulating GIP, which suggests that this cleavage influences GIP levels. Liver histology revealed reduced steatosis in ΔSirt1 mice, alongside increased glycogen accumulation and elevated glycogen synthase 2 (GYS2) levels. DESI-MS analysis of 16-month livers demonstrated increased hepatic glucose and citrate levels, with reduced palmitic and oleic acids. Expression of SREBP1c-related genes and acetyl-CoA carboxylase 1 (ACC1) was reduced, indicating suppressed de novo lipogenesis (DNL). Age was associated with increased Thr308AKT phosphorylation, which led to paradoxical maturation of SREBP1c (mSREBP1c), which was deacetylated at K294. The mutants additionally displayed increased cytoplasmic mSREBP1c and impaired nuclear staining, suggesting its cytoplasmic retention or nuclear instability, in line with the phenotypic reduction of lipid biosynthesis and storage. These findings suggest that preventing SIRT1 C-terminal cleavage preserves SIRT1 activity, reduces age-related hepatic steatosis by inhibiting SREBP1c-driven lipogenesis, and lowers caloric intake through modulation of GIP signaling

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

SUBMITTER: Mona Dvir  

LAB HEAD: Prof. Mona Dvir-Ginzberg

PROVIDER: PXD080578 | Pride | 2026-10-22

REPOSITORIES: Pride