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Hepatic Lpcat3 Accelerates Nonalcoholic Fatty Liver Disease by slut1e1-related promoting fatty acid oxidation and reducing fatty acid synthesis [MCD RNA-seq]

ABSTRACT: Non-alcoholic steatohepatitis (NASH) is a common chronic liver disease associated with metabolic disorders such as obesity, diabetes, and high cholesterol. It results in inflammation and fibrosis of liver tissue, eventually leading to cirrhosis and liver cancer. While LPCAT3 has been linked to the formation of fat cells, its role in the development of NASH is not yet fully understood. The purpose of this study was to gain insights into the mechanisms that accelerate NASH induced by LPCAT3. We utilized a genetic engineering rodent model and transcriptomics sequencing approach to explore the role and regulatory mechanism of LPCAT3 in the development of NAFLD. Approach & Results: We studied the impact of Lpcat3 deficiency on NASH progression using three distinct Lpcat3 liver-specific knockout mouse (LKO) models and conducted RNA sequencing, lipidomics, and metabolomics studies on liver samples. Human samples were obtained and analyzed for LPCAT3 expression in patients with NASH to determine its correlation with disease severity. The HepG2 and Huh-7 cell lines were utilized for in vitro analyses. We discovered that LPCAT3 expression was elevated in human NASH livers, and its expression correlated with NAFLD activity score and fibrosis stage. Lpcat3 deficiency in the mouse liver slows the development of diet-induced NASH. Lpcat3 deficiency mechanistically reduces lipid production by inhibiting lipid metabolic pathwaysDeletion of Lpcat3 significantly improved lipid accumulation in NASH mice, possibly due to the involvement of sult1e1 in lipogenesis and oxidation regulation. Moreover, the hepatic overexpression of Lpcat3 significantly intensified lipid buildup in steatotic cells, indicating that LPCAT3 plays a crucial role in the progression of NASH. Conclusions: The findings indicate that LPCAT3 regulates the participation of sult1e1 in both adipogenesis and oxidation, leading to enhanced NASH outcomes.

ORGANISM(S): Mus musculus

PROVIDER: GSE273291 | GEO | 2025/01/10

REPOSITORIES: GEO

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Project description:Background & Aims: Overnutrition is one of the major causes of non-alcoholic fatty liver disease (NAFLD) and its advanced form non-alcoholic steatohepatitis (NASH). Besides the quantity of consumed calories, distinct dietary components are increasingly recognized as important contributor to the pathogenesis of NASH. We aimed to develop and characterize a hitherto missing murine model which resembles both the pathology and nutritional situation of NASH-patients in Western societies. Methods: We developed a NASH-inducing diet (ND) enriched with sucrose, cholesterol and a high concentration of fats rich in saturated fatty acids in a composition which mimics Western food. C57Bl6/N mice were fed with the ND or control chow for 12 weeks. Biochemical, real-time polymerase chain reaction, Western Blot and immunohistochemical analyses were performed to characterize systemic and hepatic changes induced by ND-feeding. Immunohistochemistry was used to assess c-Jun levels and activation in 110 human NAFLD and control liver specimens applying tissue micro array technology. Results: ND-fed mice showed significant body weight gain, impaired glucose tolerance, elevated fasting blood glucose levels as well as decreased adiponectin and increased leptin serum levels compared to control mice. In the liver, ND-feeding led to marked steatosis, enhanced cholesterol levels, distinct signs of oxidative stress, hepatocellular damage, inflammation, activation of hepatic stellate cells, and beginning fibrosis. Transcriptome-wide hepatic gene expression analysis comparing ND-fed mice and control mice indicated main alterations in lipid metabolism and inflammatory processes. Search for over-represented transcription factor target sites among the differentially expressed genes identified AP-1 as the most likely factor to cause the transcriptional changes in ND-livers. Combining differentially expressed gene and protein-protein interaction network analysis identified c-Jun (a component of the AP-1 complex) as hub in the largest connected deregulated sub-network in ND-livers. In accordance, ND-livers revealed c-Jun-phosphorylation and nuclear translocation. Moreover, hepatic c-Jun RNA and protein expression was enhanced in ND-fed compared to control mice. Also NAFLD-patients showed enhanced hepatic c-Jun levels, which correlated with inflammation, and notably, with the degree of hepatic steatosis. Conclusions: The new dietary mouse-model shows important pathological changes also found in human NASH and indicates c-jun/AP-1 activation as critical regulator of hepatic alterations. Abundance of c-jun in NAFLD likely facilitates development and progression of NASH, and thus, c-jun appears as attractive prognostic and therapeutic target of NAFLD progression. 14-weeks old male C57BL/6N mice were fed with either regular diet or a newly designed NASH-inducing diet for 12 weeks. Hepatic gene expression levels were measured thereafter.

Project description:The pathological progression of nonalcoholic fatty liver disease (NAFLD) is driven by multiple factors, and nonalcoholic steatohepatitis (NASH) represents its progressive form. In our previous studies, we found that bicyclol had beneficial effects on NAFLD/NASH. Here we aim to investigate the underlying molecular mechanisms of the bicyclol effect on NAFLD/NASH induced by high-fat diet (HFD) feeding. A mice model of NAFLD/NASH induced by HFD-feeding for 8 weeks was used. As a pretreatment, bicyclol (200 mg/kg) was given to mice by oral gavage twice daily. Hematoxylin and eosin (H&E) stains were processed to evaluate hepatic steatosis, and hepatic fibrous hyperplasia was assessed by Masson staining. Biochemistry analyses were used to measure serum aminotransferase, serum lipids, and lipids in liver tissues. Proteomics and bioinformatics analyses were performed to identify the signaling pathways and target proteins. The real-time RT-PCR and Western blot analyses were performed to verify the proteomics data. As a result, bicyclol had a markedly protective effect against NAFLD/NASH by suppressing the increase of serum aminotransferase, hepatic lipid accumulation and alleviating histopathological changes in liver tissues. Proteomics analyses showed that bicyclol remarkably restored major pathways related to immunological responses and metabolic processes altered by HFD feeding. Consistent with our previous results, bicyclol significantly inhibited inflammation and oxidative stress pathway related indexes (SAA1, GSTM1 and RDH11). Furthermore, the beneficial effects of bicyclol were closely associated with the signaling pathways of bile acid metabolism (NPC1, SLCOLA4 and UGT1A1), cytochrome P450-mediated metabolism (CYP2C54, CYP2C70 and CYP3A25), biological processes such as metal ion metabolism (Ceruloplasmin and Metallothionein-1), angiogenesis (ALDH1A1) and immunological responses (IFI204 and IFIT3). These findings suggested that bicyclol is a potential preventive agent for NAFLD/NASH by targeting multiple mechanisms in future clinical investigations.

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Hepatic Lpcat3 Accelerates Nonalcoholic Fatty Liver Disease by slut1e1-related promoting fatty acid oxidation and reducing fatty acid synthesis [MCD RNA-seq]

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