Cholesterol can modulate mitochondrial aquaporin‐8 expression in human hepatic cells

Abstract

Hepatocyte mitochondrial aquaporin-8 (mtAQP8) works as a multifunctional membrane channel protein that facilitates the uptake of ammonia for its detoxification to urea as well as the mitochondrial release of hydrogen peroxide. Since early oligonucleotide microarray studies in liver of cholesterol-fed mice showed an AQP8 downregulation, we tested whether alterations of cholesterol content per se modulate mtAQP8 expression in human hepatocyte-derived Huh-7 cells. Cholesterol loading with methyl-β-cyclodextrin (mβCD):cholesterol complexes downregulated the proteolytic activation of cholesterol-responsive sterol regulatory element-binding protein (SREBP) transcriptions factors 1 and 2, and the expression of the target gene 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). Under such conditions, mtAQP8 mRNA and protein expressions were significantly reduced. In contrast, cholesterol depletion using mβCD alone increased SREBP-1 and 2 activation and upregulated HMGCR and mtAQP8 mRNA and protein expressions. The results suggest that cholesterol can regulate transcriptionally human hepatocyte mtAQP8 expression likely via SREBPs. The functional implications of our findings are discussed. © 2017 IUBMB Life, 69(5):341-346, 2017.

Cell organelles as targets of mammalian cadmium toxicity

“…Moreover, additional metals have been shown to affect AQP function: Pb 2+ increased water permeability of AQP4 in astrocytes (Gunnarson et al 2005), albeit in a calcium calmodulin dependent manner, and Hg 2+ increased plant AQP functionality (Frick et al 2013) thus strengthening a role for toxic metal-induced AQP functionalization in mitochondria. To this end, mitochondrial AQP8 expression is negatively impacted by mitochondrial oxidative stress (Liu et al 2018a) and cholesterol depletion (Danielli et al 2017). In addition, overexpression of mitochondrial AQP8 increases de novo cholesterol synthesis by increasing expression of the sterol regulatory element-binding protein 2 (SREBP-2) transcription factor and the ratelimiting enzyme HMGCR (Danielli et al 2019), suggesting cholesterol is required for AQP8 function.…”

Aquaporin Membrane Channels in Oxidative Stress, Cell Signaling, and Aging: Recent Advances and Research Trends

“…Another as-yet-unexplored area of research is the role that mtAQP8-mediated H 2 O 2 may play in hepatocyte physiology. We have recently provided evidence suggesting that hepatocyte mtAQP8 expression can be modulated by cholesterol via sterol regulatory element-binding protein (SREBP) transcription factors; that is, mtAQP8 is upregulated in cholesterol-depleted cells and downregulated in cholesterol-loaded cells [ 57 ]. As H 2 O 2 has been described to stimulate hepatocyte cholesterogenesis via SREBPs [ 58 ], our finding might suggest that mtAQP8 plays a role in SREBP-controlled cholesterol biosynthesis.…”

Importance of cholesterol-rich microdomains in the regulation of Nox isoforms and redox signaling in human vascular smooth muscle cells

“…Similar to many other studies [70][71][72][73][74] , we used a pharmacological approach to disrupt lipid rafts/caveolae in human VSMCs. However this approach does have limitations because MCD has been shown to disrupt cholesterol-rich domains beyond the plasma membrane 70,71 . In particular MCD influences membranes of subcellular organelles, including mitochondria, and accordingly we can not exclude the potential role of other sources, such as mitochondria, for ROS in our experimental paradigm.…”