Abstract
The active spliced form of X-box-binding protein 1 (XBP1s) is a key modulator of ER stress, but the functional role of its post-translational modification remains unclear. Here, we demonstrate that XBP1s is a deacetylation target of Sirt6 and that its deacetylation protects against ER stress-induced hepatic steatosis. Specifically, the abundance of acetylated XBP1s and concordant hepatic steatosis were increased in hepatocyte-specific Sirt6 knockout and obese mice but were decreased by genetic overexpression and pharmacological activation of Sirt6. Mechanistically, we identified that Sirt6 deacetylated a transactivation domain of XBP1s at Lys257 and Lys297 and promoted XBP1s protein degradation through the ubiquitin-proteasome system. Overexpression of XBP1s, but not its deacetylation mutant 2KR (K257/297R), in mice increased lipid accumulation in the liver. Importantly, in liver tissues obtained from patients with nonalcoholic fatty liver disease (NAFLD), the extent of XBP1s acetylation correlated positively with the NAFLD activity score but negatively with the Sirt6 level. Collectively, we present direct evidence supporting the importance of XBP1 acetylation in ER stress-induced hepatic steatosis.
Highlights
1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Introduction Nonalcoholic fatty liver disease (NAFLD) is a disorder characterized by hepatic fat accumulation that can progress to nonalcoholic steatohepatitis (NASH)[1]
Consistent with previous reports[8], hepatic triglyceride (TG) levels were highly increased, whereas the plasma TG level gradually decreased (Fig. S1e), and these changes were accompanied by increased expression of unfolded protein response (UPR) signaling molecules, including XBP1s, p-protein kinase-like ER kinase (PERK), p-eIF2α and activating transcription factor 6 (ATF6) (p50) (Fig. S1f)
Sirt[6] ameliorates hepatic endoplasmic reticulum (ER) stress by deacetylating XBP1s to improve fat accumulation, apoptosis, and insulin resistance in hepatocytes. The plausibility of this hypothesis was derived from the previous finding that prolonged and unmitigated ER stress is tightly linked to NAFLD7,31 and that hepatic insulin resistance and steatosis in NAFLD are aggravated by Sirt[6] deficiency[24,25]
Summary
Nonalcoholic fatty liver disease (NAFLD) is a disorder characterized by hepatic fat accumulation (steatosis) that can progress to nonalcoholic steatohepatitis (NASH)[1]. During chronic high-calorie diet feeding, an increased demand for protein synthesis leads to the disruption of endoplasmic reticulum (ER) homeostasis, which is termed ER stress[2]. ER stress, in turn, induces the unfolded protein response (UPR) that directs unfolded or misfolded proteins to molecular chaperones to be refolded or degraded. The UPR is initiated by three ER stress sensor proteins: inositol-requiring enzyme 1α (IRE1α), protein kinase-like ER kinase (PERK), and activating transcription factor 6 (ATF6)[3]. Upon exposure to ER stressors, IRE1α undergoes dimerization and transautophosphorylation, which activates its endoribonuclease activity and cleaves XBP1 mRNA, leading to the translation of a spliced form of XBP1 (XBP1s)[4]. XBP1s upregulates the expression of specific genes involved in ER biogenesis and protein secretion, as well as molecular chaperones[5]
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