The Interplay of TGF-ß1 and Cholesterol Orchestrating Hepatocyte Cell Fate, EMT, and Signals for HSC Activation.
Cell Mol Gastroenterol Hepatol
; 17(4): 567-587, 2024.
Article
em En
| MEDLINE
| ID: mdl-38154598
ABSTRACT
BACKGROUND & AIMS:
Transforming growth factor-ß1 (TGF-ß1) plays important roles in chronic liver diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). MASLD involves various biological processes including dysfunctional cholesterol metabolism and contributes to progression to metabolic dysfunction-associated steatohepatitis and hepatocellular carcinoma. However, the reciprocal regulation of TGF-ß1 signaling and cholesterol metabolism in MASLD is yet unknown.METHODS:
Changes in transcription of genes associated with cholesterol metabolism were assessed by RNA sequencing of murine hepatocyte cell line (alpha mouse liver 12/AML12) and mouse primary hepatocytes treated with TGF-ß1. Functional assays were performed on AML12 cells (untreated, TGF-ß1 treated, or subjected to cholesterol enrichment [CE] or cholesterol depletion [CD]), and on mice injected with adenovirus-associated virus 8-control/TGF-ß1.RESULTS:
TGF-ß1 inhibited messenger RNA expression of several cholesterol metabolism regulatory genes, including rate-limiting enzymes of cholesterol biosynthesis in AML12 cells, mouse primary hepatocytes, and adenovirus-associated virus-TGF-ß1-treated mice. Total cholesterol levels and lipid droplet accumulation in AML12 cells and liver tissue also were reduced upon TGF-ß1 treatment. Smad2/3 phosphorylation after 2 hours of TGF-ß1 treatment persisted after CE or CD and was mildly increased after CD, whereas TGF-ß1-mediated AKT phosphorylation (30 min) was inhibited by CE. Furthermore, CE protected AML12 cells from several effects mediated by 72 hours of incubation with TGF-ß1, including epithelial-mesenchymal transition, actin polymerization, and apoptosis. CD mimicked the outcome of long-term TGF-ß1 administration, an effect that was blocked by an inhibitor of the type I TGF-ß receptor. In addition, the supernatant of CE- or CD-treated AML12 cells inhibited or promoted, respectively, the activation of LX-2 hepatic stellate cells.CONCLUSIONS:
TGF-ß1 inhibits cholesterol metabolism whereas cholesterol attenuates TGF-ß1 downstream effects in hepatocytes.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Fator de Crescimento Transformador beta1
/
Fígado Gorduroso
Limite:
Animals
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article