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- Title
Perilipin 5 deletion protects against nonalcoholic fatty liver disease and hepatocellular carcinoma by modulating lipid metabolism and inflammatory responses.
- Authors
Mass-Sanchez, Paola Berenice; Krizanac, Marinela; Štancl, Paula; Leopold, Marvin; Engel, Kathrin M.; Buhl, Eva Miriam; van Helden, Josef; Gassler, Nikolaus; Schiller, Jürgen; Karlić, Rosa; Möckel, Diana; Lammers, Twan; Meurer, Steffen K.; Weiskirchen, Ralf; Asimakopoulos, Anastasia
- Abstract
The molecular mechanisms underlying the transition from nonalcoholic fatty liver disease (NAFLD) to hepatocellular carcinoma (HCC) are incompletely understood. During the development of NAFLD, Perilipin 5 (PLIN5) can regulate lipid metabolism by suppressing lipolysis and preventing lipotoxicity. Other reports suggest that the lack of PLIN5 decreases hepatic injury, indicating a protective role in NAFLD pathology. To better understand the role of PLIN5 in liver disease, we established mouse models of NAFLD and NAFLD-induced HCC, in which wild-type and Plin5 null mice were exposed to a single dose of acetone or 7,12-dimethylbenz[a]anthracene (DMBA) in acetone, followed by a 30-week high-fat diet supplemented with glucose/fructose. In the NAFLD model, RNA-seq revealed significant changes in genes related to lipid metabolism and immune response. At the intermediate level, pathways such as AMP-activated protein kinase (AMPK), signal transducer and activator of transcription 3 (STAT3), c-Jun N-terminal kinase (JNK), and protein kinase B (AKT) were blunted in Plin5-deficient mice (Plin5−/−) compared to wild-type mice (WT). In the NAFLD-HCC model, only WT mice developed liver tumors, while Plin5−/− mice were resistant to tumorigenesis. Furthermore, only 32 differentially expressed genes associated with NALFD progession were identified in Plin5 null mice. The markers of mitochondrial function and immune response, such as the peroxisome proliferator‐activated receptor-γ, coactivator 1‐α (PGC-1α) and phosphorylated STAT3, were decreased. Lipidomic analysis revealed differential levels of some sphingomyelins between WT and Plin5−/− mice. Interestingly, these changes were not detected in the HCC model, indicating a possible shift in the metabolism of sphingomelins during carcinogenesis.
- Subjects
NON-alcoholic fatty liver disease; LIPOLYSIS; LIPID metabolism; INFLAMMATION; HEPATOCELLULAR carcinoma; PERILIPIN
- Publication
Cell Death Discovery, 2024, Vol 10, Issue 1, p1
- ISSN
2058-7716
- Publication type
Article
- DOI
10.1038/s41420-024-01860-4