Kangwon National University

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.

In this study, heterogeneous biochar catalysts derived from spent coffee grounds (HCBCs) and walnut shells (HWBCs) were synthesized at three pyrolysis temperatures (500 °C (HCBC500, HWBC500), 650 °C (HCBC650, HWBC650), and 800 °C (HCBC800, HWBC800)) to elucidate effects of changes in the aromatization degree determining electron exchange capacity (EEC) of heterogeneous biochar catalysts on the degradation of naproxen (NPX) via the electron transfer-mediated activation of peroxydisulfate (PDS). The greater EEC values of highly aromatic HCBCs and HWBCs produced at higher pyrolysis temperatures led to increased degradation efficiencies of NPX by the HCBCs/PDS and HWBCs/PDS systems. The HCBC800/PDS system achieved the highest degradation efficiency of NPX, at 80.9%, compared to 16.4-48.1% for other systems. These observations highlight that the EEC relying on the aromatization degree of heterogeneous biochar catalysts is a key factor governing the degradation of NPX via the electron transfer-mediated activation of PDS. In the HCBC800/PDS system, electrophilic decarboxylation induced by superoxide-derived singlet oxygen was mainly responsible for the degradation of NPX rather than hydroxyl radical-driven electrophilic hydroxylation. Moreover, the HCBC800/PDS system exhibited excellent reuse efficiency (≥73.2%) for the degradation of NPX over four consecutive cycles. Although increases in bioaccumulation potential and mutagenicity were detected for some degradation intermediates of NPX produced via the HCBC800/PDS system, most of them were less harmful to aquatic ecosystems. Therefore, HCBC800 could be a promising option as a carbonaceous material-based heterogeneous catalyst to activate PDS via the electron transfer for eliminating NPX.