Hepatic management of toxic sterols after acute deletion of Cyp51 from cholesterol synthesis

Kreft, Tinkara (avtor), Blagotinšek Cokan, Kaja (avtor), Skubic, Cene (avtor), Režen, Tadeja (avtor), Perše, Martina (avtor), Wechtersbach, Karmen (avtor), Kojc, Nika (avtor), Jeruc, Jera (avtor), Debeljak, Željko (avtor), Heffer, Marija (avtor), Matz-Soja, Madlen (avtor), Rozman, Damjana (avtor)

Lanosterol 14α-demethylase (CYP51), a key enzyme in cholesterol synthesis, is essential for normal liver function. Reduced CYP51 activity leads to metabolism-associated liver disease and ultimately hepatocellular carcinoma, yet the hepatocellular processes most affected and their crosstalk with other liver cell types remain poorly defined. Here, we present a new inducible, liver-specific Cyp51 knockout mouse model (iLKO) designed to study how acute disruption of cholesterol synthesis is managed in the adult liver. Doxycycline-inducible deletion minimizes developmental confounders of albumin-Cre models and enables isolation of viable primary hepatocytes. iLKO hepatocytes and liver tissue showed efficient CYP51 depletion with marked accumulation of lanosterol and 24,25-dihydrolanosterol, while hepatic cholesterol levels remained unchanged or only mildly reduced, indicating compensatory uptake and/or pathway rerouting. Histology and transmission electron microscopy (TEM) revealed hepatomegaly with mild portal inflammation, ductular reaction, endoplasmic reticulum (ER) dilation, mitochondrial swelling, and increased nuclear lipid droplets, consistent with adaptation to ER stress but without overt fibrosis at the studied time points. Notably, crystal-like inclusions - particularly in Kupffer cells - were observed. Although MALDI-TOF MS imaging could not determine their exact composition, their presence in the context of toxic sterol overload strongly suggests non-cholesterol sterol crystallization as a previously unrecognized trigger of inflammation. In summary, the iLKO model allows dissection of sterol toxicity independently of developmental effects and provides mechanistic insight into how disrupted cholesterol synthesis in adult hepatocytes initiates sterol-driven cellular stress and inflammation that predispose to metabolism-associated liver disease and hepatocellular carcinoma.

• Jezik: Angleški jezik
• Ključne besede: CYP51, cholesterol metabolism, crystals, cytochrome P450, lanosterol 14α-demethylase, lipid droplets, liver, mouse model, sterol
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: MF - Medicinska fakulteta
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2026
• Št. strani: 17 str.
• Številčenje: Vol. 302, iss. 3, art. 111188
• PID: 20.500.12556/RUL-179501
• UDK: 577.2
• ISSN pri članku: 1083-351X
• DOI: 10.1016/j.jbc.2026.111188
• COBISS.SI-ID: 267520771
• Datum objave v RUL: 16.02.2026

Gradivo je del revije

• Naslov: Journal of biological chemistry
• Skrajšan naslov: J. biol. chem.
• Založnik: American Society for Biochemistry and Molecular Biology
• ISSN: 1083-351X
• COBISS.SI-ID: 19301415

Licence

• Licenca: CC BY-NC-ND 4.0, Creative Commons Priznanje avtorstva-Nekomercialno-Brez predelav 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by-nc-nd/4.0/deed.sl
• Opis: Najbolj omejujoča licenca Creative Commons. Uporabniki lahko prenesejo in delijo delo v nekomercialne namene in ga ne smejo uporabiti za nobene druge namene.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: CYP51, presnova holesterola, kristali, citokrom P450, lanosterol 14α-demetilaza, lipidne kapljice, jetra, mišji model, sterol