High-Calorie Diet Accelerates the Liver Tissue Degeneration and Induces Subcutaneous White-to-Brown Fat Conversion in
Qussai Abbas1, Elena S Petrova2, Nadezhda V Tsymbalenko3
1Research Center of Advanced Functional Materials and Laser Communication Systems, ADTS Institute, ITMO University, St. Petersburg, Russia.
Background:
Wilson disease (WD) is a hereditary autosomal-recessive disorder of copper metabolism caused by mutations in the ATP7B gene, which also leads to dysregulation of lipid metabolism. In Atp7b-/--mice, a high-calorie diet (HCD) aggravates WD symptoms. However, it remains unknown whether HCD induces similar effects in asymptomatic Atp7b+/--heterozygotes.
Objectives:
This study aimed to determine whether HCD induces a WD-like phenotype in Atp7b+/--mice.
Methods:
Five-month-old male C57BL/6 Atp7b+/+ and Atp7b+/--mice (n = 3-6/group) were fed either standard diet (SD, 326 kcal/100 g) or HCD (420 kcal/100g) for 18 wk. Serum copper, glucose, insulin, lipid profile, and oxidase activity were measured. Liver, subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) were analyzed via histology and electron microscopy. Expression of copper metabolism-related genes (CMRGs) was assessed by RT-qPCR (Quantitative Real Time PCR). MANOVA with Tukey post hoc test was used for statistical analysis using the R software.
Results:
Genotype had no effect on concentrations of copper, triglycerides, total cholesterol, high-density lipoprotein (HDL) cholesterol/non-HDL cholesterol, low-density lipoprotein (LDL) cholesterol/non-LDL cholesterol, atherogenicity index, or oxidase activity. Glucose concentrations were significantly reduced in Atp7b+/-(HCD)-mice (3.9 compared with 7.6 mM/L, P < 0.05), whereas insulin concentrations were elevated in Atp7b+/+(HCD)-mice (0.5 compared with 0.1 μg/L, P < 0.05). Liver steatosis and fibrosis were found in Atp7b+/-(SD) and worsened by HCD. Adipocyte hypertrophy was observed in both SAT and VAT under HCD [2734 μm2 in Atp7b+/+(HCD) and 1382 μm2 in Atp7b+/-(HCD) compared with 1040 μm2 in Atp7b+/+(SD) and 1934 μm2 in Atp7b+/-(SD), P < 0.05]. White-to-brown fat conversion was noted in the SAT of Atp7b+/-(HCD)-mice. In the liver, HCD reduced Ctr1 and Cp gene expression by 60% and 30%, respectively (P < 0.05); in SAT, all assessed CMRGs were upregulated by 50%-85% (P < 0.05); whereas no changes were detected in VAT.
Conclusions:
Atp7b+/-(SD)-mice display hepatic and adipose abnormalities, aggravated by an HCD, suggesting that WD heterozygotes may be diet sensitive, highlighting the relevance of dietary management to prevent metabolic and hepatic complications.
