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Knockdown of PPARγ can ameliorate benzbromarone-induced obesity-specific drug-induced liver injury

ABSTRACT: Objective: Benzbromarone (BBR) is an effective uric acid-lowering drug. However, it can induce severe liver damage in some patients. Studies have shown that BBR specifically exacerbates hepatic steatosis in obese individuals, leading to aggravated liver injury. The exact mechanism behind this phenomenon remains unclear. Methods: db/db mice were divided into four groups: Control, BBR administration (BBR), Pparg knockdown (Pparg-KD), and BBR administration with Pparg knockdown (BBR + Pparg-KD). One week after AAV8-shRNA-Pparg virus injection, mice were orally administered BBR for four weeks, and changes in blood glucose and body weight were measured. Subsequently, samples were collected, and plasma lipid levels, hepatic lipid content, and liver function parameters were determined. RNA-seq was performed to assess changes in the hepatic gene expression profile and analyze the protective effect of PPARγ knockdown on BBR-induced drug-induced liver injury. Results: Mice in the BBR group exhibited more severe levels of plasma lipids, hepatic lipids, and liver function parameters compared to the Control group. However, mice in the BBR + Pparg-KD group showed significant improvements in these indicators compared to the BBR group. Transcriptomic analysis revealed that BBR administration upregulated the expression of various lipid synthesis-related genes, primarily associated with the PPAR signaling pathway. Furthermore, PPARγ knockdown reversed the increased expression of these lipid synthesis genes. This suggests that PPARγ knockdown has a significant protective effect against BBR-induced drug-induced liver injury. Conclusion: Hepatocyte-specific knockdown of PPARγ can protect against BBR-induced exacerbation of hepatic steatosis and liver injury by inhibiting the promotion of lipid synthesis through PPARγ activation.

ORGANISM(S): Mus musculus

PROVIDER: GSE274748 | GEO | 2025/01/29

REPOSITORIES: GEO

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Project description:Fat accumulation, de novo lipogenesis, and glycolysis are key contributors to hepatocyte reprogramming and the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). The molecular mechanisms affected by steatosis and inflammation in the obese states remain unknown. Here we report that obesity leads to dysregulated expression of protein-tyrosine phosphatases (PTPs) in the liver. Protein Tyrosine Phosphatase Receptor Kappa (PTPRK) was increased in hepatocytes by steatosis and inflammation in humans and mice, and positively correlates with PPARγ-induced lipogenic signalling. Mechanistically, PTPRK-PPARγ upregulation by fat accumulation is dependent upon Notch signalling in mouse primary hepatocytes. PTPRK knockout mice have reduced fat accumulation in adipose tissue and liver after exposure to an obesogenic diet. Phosphoproteomic analysis in isolated hepatocytes and hepatic metabolomics identified specific phosphotyrosine residues in fructose-1,6 bisphosphatase-1 and glycolysis regulation as targets of PTPRK. These changes in glycolysis and de novo lipogenesis revealed PTPRK-dependent metabolic reprogramming in hepatocytes. Moreover, hepatoma cell lines showed reduced colony-forming ability after PTPRK silencing in vitro, and PTPRK knockout mice developed smaller tumours after diethylnitrosamine-induced hepatocarcinogenesis in vivo. Computational modelling identified potential PTPRK inhibitors, which selectively reduced PTPRK activity. The compounds decreased glycolytic rates in hepatoma cell lines, PPARγ expression in primary hepatocytes and steatosis in obese mice. In conclusion, our study defines a novel mechanism for the development of MASLD, revealing a key role of PTPRK on hepatic glycolysis regulation with implications in lipid metabolism, and liver tumour development. We propose PTPRK as a potential target for metabolic liver dysfunction, and the identified inhibitors may represent promising candidates for therapy in obesity-associated liver diseases.

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Knockdown of PPARγ can ameliorate benzbromarone-induced obesity-specific drug-induced liver injury

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