Perilipin 5 deletion protects against nonalcoholic fatty liver disease and hepatocellular carcinoma by modulating lipid metabolism and inflammatory responses
The molecular mechanisms underlying nonalcoholic fatty liver disease (NAFLD) transition to hepatocellular carcinoma (HCC) are incompletely understood. During NAFLD development, Perilipin 5 (PLIN5) can regulate lipid metabolism by suppressing lipolysis and preventing lipotoxicity. Other reports suggest that 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 protein level, signaling pathways such as AMP-activated protein kinase (AMPK), signal transducer and activator of transcription 3 (STAT3), Janus kinase (JNK) and protein kinase B (AKT) were blunted in Plin5 deficient (Plin5-/-) mice compared to wild type mice (WT). In the NAFLD-HCC model, only WT mice developed hepatic tumors, while Plin5-/- mice were resistant to tumorigenesis. Furthermore,  only 32 differentially expressed genes were identified that were associated with NAFLD progession in Plin5 null mice. Markers of mitochondrial function and immune response such as the peroxisome proliferator-activated receptor-?, coactivator 1-a (PGC-1a) and pSTAT3 were decreased. Lipidomics 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. Overall design: To investigate the roles of Plin5 depletion in a NAFLD and NAFLD-HCC model, we induced both pathologies in WT and Plin5 KO mice and performed RNA-seq analysis to check their transcriptional profiles.