Search Results (5)

Metabolically Dysfunctional-Associated Steatotic Liver Disease (MASLD) affects both metabolically healthy obese (MHO) individuals and metabolically unhealthy lean (MUL) individuals. Key genes linked to liver dysfunction, such as MLXIPL, PPARA, and FGF21, are under-researched in humans. We aimed to evaluate the ChREBP–PPARα–FGF21 axis in relation to metabolic liver dysfunction in MHO and MUL individuals. Liver histopathology, biochemical data, anthropometric measurements, mRNA expression as analyzed by qPCR, and heatmap visualization were utilized to identify relationships among variables and discern gene expression patterns. ChREBP–PPARA–FGF21 genes were analyzed in liver, subcutaneous (SAT), and omental adipose tissue (OAT) biopsies from 55 subjects, including metabolically unhealthy obese (MUO), MHO, MUL, and metabolically healthy lean (MHL) subjects as controls. The MHL, MUL, MHO, and MUO groups showed a gradual increase in liver PPARα, with a downward trend in ChREBPβ levels in SAT (p < 0.05). Liver ChREBPβ positively correlated with insulin resistance and FGF21. Levels of OAT ChREBPβ showed a negative correlation with anthropometric measurements and serum insulin levels. These findings suggest coordinated regulation under metabolic stress. Increased FGF21 expression in the MUL and MUO groups may aid as a metabolic biomarker of impaired energy homeostasis and compensatory hepatic response. Full article

The Carbohydrate-Responsive Element-Binding Protein (ChREBP) is a glucose-sensitive transcription factor that regulates the carbohydrate and lipid metabolism. We investigated its cell-type-specific role in hepatocarcinogenesis using a chemically induced mouse model. Additionally, we examined the functions of its isoforms, ChREBPα and ChREBPβ. After the diethylnitrosamine (DEN) administration, we analyzed hepatocellular adenomas and carcinomas in systemic ChREBP-knockout (KO), hepatocyte-specific ChREBP-KO (L-KO), and wildtype (WT) mice at 4, 12, and 36 weeks using histology, morphometry, proliferation measurements, immunohistochemistry, a Western blot, and a quantitative PCR. Tumors developed 36 weeks after the DEN administration in 27% of WT mice but less frequently in KO (18%) and L-KO (9%) mice. However, preneoplastic foci were less common in KO mice but not in L-KO mice (39% vs. 9%; p < 0.05). L-KO hepatocytes exhibited lower proliferation, while KO tumors showed the downregulation of AKT/mTOR signaling, glycolysis, and lipogenesis compared to WT tumors. Our results showed that the liver-specific loss of ChREBPα, while ChREBPβ remained active, significantly reduced the tumor progression, suggesting an oncogenic role for ChREBPα. In contrast, the systemic knockout of both ChREBPα and ChREBPβ reduced the tumor initiation but did slightly prevent tumor progression, indicating that ChREBPβ may exert tumor-suppressive functions. Full article

Our previous studies have reported the effect of swietenine (a major bioactive component of Swietenia macrophylla seeds) in reversing and potentiating the effect of metformin in hyperglycemia and hyperlipidaemia in diabetic rats. Moreover, we reported that the anti-inflammatory effect of swietenine is mediated via the activation of nuclear factor erythroid 2-related factor 2 (Nrf2). This study evaluated the effect of swietenine and its mechanisms in nonalcoholic fatty liver disease (NAFLD) in high-fat diet/streptozotocin-induced diabetic mice. The effect was assessed by determining blood biochemical parameters (glucose, cholesterol, triglycerides, alanine transaminase (ALT), asparate transaminase (AST), alkaline phosphatase (ALP), glutathione (GSH), total antioxidant capacity (TAC), and malondialdehyde (MDA)) and liver biochemical parameters (liver index, cholesterol, and triglycerides). Hepatic lipid accumulation (initial causative factor in NAFLD) was determined by oil-O-red staining. Gene expression (qPCR) and immunohistochemical studies were performed to elucidate the mechanism of swietenine’s effect in NAFLD. The critical regulators (genes and proteins) involved in lipogenesis (ACLY, ACC1, FASN, SREBP1c, and ChREBPβ) and oxidative stress (Nrf2, NQO-1 and HO-1) pathways were determined. In mice fed with a high-fat diet followed by streptozotocin injection, the liver cholesterol, triglycerides, and lipids were elevated. These increases were reversed by the oral administration of swietenine, 80 mg/kg body weight, on alternate days for eight weeks. Gene expression and immunohistochemical studies showed that swietenine reversed the elevated levels of crucial enzymes of lipogenesis (ACLY, ACC1 and FASN) and their master transcription factors (SREBP1c and ChREBPβ). Furthermore, swietenine activated the Nrf2 antioxidant defense mechanism, as evidenced by the upregulated levels of Nrf2, NQO-1, and HO-1. It is concluded that swietenine shows beneficial effects in diabetes-induced NAFLD via inhibiting lipogenesis and activating the Nrf2 pathway. Full article

Fructose consumption is associated with metabolic syndrome (MeS). Dysregulated lipid metabolism and ectopic lipid accumulation, such as in “fatty liver’’, are pivotal components of the syndrome. MeS is also associated with chronic kidney disease (CKD). The aim of this study was to evaluate kidney fructose metabolism and whether the addition of fructose leads to intrarenal fat accumulation. Sprague Dawley rats were fed either normal chow (Ctrl) or a high-fructose diet (HFrD). MeS features such as blood pressure and metabolic parameters in blood were measured. The kidneys were harvested for ChREBPβ and de novo lipogenesis (DNL) gene expression, triglyceride content and histopathology staining. HK2 (human kidney) cells were treated with fructose for 48 h and gene expression for ChREBPβ and DNL were determined. The HFrD rats exhibited higher blood pressure, glucose and triglyceride levels. The kidney weight of the HFrD rats was significantly higher than Ctrl rats. The difference can be explained by the higher triglyceride content in the HFrD kidneys. Oil red staining revealed lipid droplet formation in the HFrD kidneys, which was also supported by increased adipophilin mRNA expression. For ChREBPβ and its downstream genes, scd and fasn, mRNA expression was elevated in the HFrD kidneys. Treating HK2 cells with 40 mM fructose increased the expression of ChREBPβ. This study demonstrates that fructose consumption leads to intrarenal lipid accumulation and to the formation of a “fatty kidney”. This suggests a potential mechanism that can at least partially explain CKD development in fructose-induced MeS. Full article

Liver X receptors (LXRα/β) and carbohydrate response element-binding proteins (ChREBPα/β) are key players in the transcriptional control of hepatic de novo lipogenesis. LXRα/β double knockout (LXRα^−/−/β^−/−) mice have reduced feeding-induced nuclear O-linked N-acetylglucosamine (O-GlcNAc) signaling, ChREBPα activity, and lipogenic gene expression in livers, suggesting important roles for LXRs in linking hepatic glucose utilization to lipid synthesis. However, the role of LXRs in fructose-induced ChREBP activation and lipogenesis is currently unknown. In this study, we studied the effects of high fructose or high glucose feeding on hepatic carbohydrate metabolism and lipogenic gene expression in livers from fasted (24 h) and fasted-refed (12 h) wild type and LXRα knockout (LXRα^−/−) mice. Hepatic lipogenic gene expression was reduced in glucose fed, but not fructose fed LXRα^−/− mice. This was associated with lower expression of liver pyruvate-kinase (L-pk) and Chrebpβ, indicating reduced ChREBPα activity in glucose fed, but not fructose fed mice. Interestingly, ChREBP binding to the L-pk promoter was increased in fructose fed LXRα^−/− mice, concomitant with increased glucose-6-phosphatase (G6pc) expression and O-GlcNAc modified LXRβ, suggesting a role for LXRβ in regulating ChREBPα activity upon fructose feeding. In conclusion, we propose that LXRα is an important regulator of hepatic lipogenesis and ChREBPα activity upon glucose, but not fructose feeding in mice. Full article