Selisistat

Dysregulation of lipid homeostasis pathway causes many liver diseases, including hepatic steatosis. One of the primary factors contributing to lipid accumulation is fatty acid uptake by the liver. Transmembrane protein 135 (TMEM135), which exists in mitochondria and peroxisomes, participates in intracellular lipid metabolism. This study aims to investigate the role of TMEM135 on regulating cellular lipid import in the liver.

We used in vivo, ex vivo, and in vitro models of steatosis. TMEM135 knockout (TMEM135KO) and wild type (WT) mice were fed a high-fat diet (HFD) to induce hepatic steatosis. Primary mouse hepatocytes and AML12 cells were treated with free fatty acid (FFA). Additionally, TMEM135-deficient stable cells and overexpressed cells were established using AML12 cells.

TMEM135 deficiency mitigated lipid accumulation in the liver of HFD-fed TMEM135KO mice. TMEM135-depleted primary hepatocytes and AML12 cells exhibited less lipid accumulation when treated with FFA compared to control cells, as shown as lipid droplets. Consistently, the effect of TMEM135 depletion on lipid accumulation was completely reversed under TMEM135 overexpression conditions. CD36 expression was markedly induced by HFD or FFA, which was reduced by TMEM135 depletion. Among the SIRT family proteins, only SIRT1 expression definitely increased in the liver of HFD-fed TMEM135KO mice along with a significant increase in NAD⁺/NADH ratio. However, inhibition of SIRT1 in TMEM135-depleted cells using siSIRT1 or the SIRT1 inhibitor EX-527 resulted in an increase of CD36 expression and consequent TG levels.

TMEM135 depletion attenuates CD36 expression in a SIRT1-dependent manner, thereby reducing cellular lipid uptake and hepatic steatosis.

Parkinson's disease (PD) is typically marked by motor dysfunction accompanied by loss of dopaminergic (DA) neurons and aggravated oxidative stress in the substantia nigra pars compacta (SNpc). Atractylenolide-I (ATR-I) is a potent antioxidant sesquiterpene with neuroprotective properties. However, whether ATR-I plays a neuroprotective role against oxidative stress in PD remains unclear. The objective of this study was to explore the mechanism of antioxidant action of ATR-I in PD models both in vivo and in vitro. Here, we show that ATR-I alleviated motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice. Moreover, ATR-I treatment effectively reduced DA neuron loss and increased tyrosine hydroxylase expression in the SNpc of MPTP-induced mice. Additionally, ATR-I inhibited oxidative stress (as manifested by elevated superoxide dismutase and glutathione peroxidase activities, and reduced malondialdehyde content) in MPTP-induced mice and attenuated reactive oxygen species levels in 1-methyl-4-phenylpyridinum (MPP⁺)-treated SH-SY5Y cells. Finally, ATR-I upregulated expressions of silent information regulator 1 (SIRT1), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), NF-E2-related factor-2 (Nrf2), and heme oxygenase-1 in MPTP-induced mice and MPP⁺-treated SH-SY5Y cells, but had little effect on these factors in the presence of the SIRT1 inhibitor EX527. Taken together, these findings indicated that the important antioxidant role of ATR-I in MPTP/MPP⁺-mediated oxidative stress and the pathogenesis of PD through the SIRT1/PGC-1α/Nrf2 axis, highlighting its potential as a therapeutic option for PD.