Sirtuin 6 activator UBCS039 ameliorates hepatic lipogenesis through liver X receptor deacetylation

Histone deacetylase sirtuin 6 (SIRT6) regulates hepatic lipogenesis by modulating key transcription factors, such as liver X receptor (LXR) and sterol regulatory element binding transcription factor 1 (SREBF1). Despite its potential role in the regulation of hepatic lipogenesis, SIRT6 activators that inhibit hepatic lipogenesis and ameliorate steatotic liver diseases have not been developed yet. We investigated the effects of UBCS039, a selective SIRT6 activator, on lipogenic gene expression and inflammation in hepatocytes. Analysis of publicly available RNA sequencing datasets revealed significant induction of LXR-regulated lipogenic genes in patients with nonalcoholic fatty liver disease. In hepatocytes, LXR agonists induced LXR expression and its downstream lipogenic regulator SREBF1, both of which were suppressed by UBCS039 pretreatment. UBCS039 promoted the deacetylation of LXR and reduced its transcriptional activity, leading to the suppressed expression of SREBF1 in hepatocytes. UBCS039 inhibited the expression of SREBF1-regulated lipogenic genes and mitigated lipid accumulation in hepatocytes. SIRT6 knockdown reversed the inhibitory effects of UBCS039 on LXR and SREBF1, confirming that UBCS039 inhibited the LXR-SREBF1 pathway through SIRT6 activation. Furthermore, UBCS039 repressed NF-κB p65 expression induced by treatment with lipopolysaccharide, palmitic acid, and tert-butyl hydroperoxide, a combination that mimics steatosis-associated lipotoxic inflammatory conditions. UBCS039 could attenuate LXR agonist-induced hepatic steatosis in mice in vivo. In conclusion, pharmacological activation of SIRT6 by UBCS039 suppressed lipogenic gene expression and inflammation in hepatocytes, highlighting its potential for alleviating steatotic liver disease.