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Perturbations in lipid metabolism and gut microbiota composition precede cardiac dysfunction in a mouse model of
Ying Liu1, Carine Fillebeen2, Anik Forest3
1Department of Biology, York University, Toronto, Ontario, Canada.
Insights
Altered lipid metabolism and gut microbiota changes in thalassemia mice may drive cardiomyopathy. Specific lipid and microbial alterations could serve as early biomarkers or therapeutic targets for this heart condition.
Area of Science:
- Biochemistry
- Cardiology
- Microbiology
Background:
- Cardiomyopathy is a serious complication of thalassemia, but its molecular causes are not fully understood.
- Altered lipid metabolism is investigated as a potential early factor in thalassemia-associated cardiomyopathy.
Purpose of the Study:
- To investigate if altered lipid metabolism is an early driver of cardiomyopathy in the Th3/+ mouse model of thalassemia.
- To identify potential early biomarkers or therapeutic targets for preventing cardiomyopathy in beta-thalassemia.
Main Methods:
- Utilized the Th3/+ mouse model of thalassemia.
- Performed untargeted lipidomics to analyze circulating lipid species.
- Conducted 16S rRNA gene profiling to assess intestinal microbiota composition.
Main Results:
- Th3/+ mice showed anemia, iron overload, and metabolic defects, particularly in males, with altered cardiac function.
- Significant alterations in 35 lipid species were observed, including changes in triglycerides and phosphatidylcholines.
- Specific lipids (PC(16:0_14:0), GlcCer(d18:1/24:0)) correlated with iron overload and cardiac hypertrophy.
- Intestinal microbiota alterations were identified, with specific bacterial genera correlating with certain lipid species.
Conclusions:
- Perturbations in lipid metabolism and gut microbiota occur in Th3/+ mice.
- Identified specific lipid and microbial factors that may serve as early biomarkers or therapeutic targets for thalassemia-induced cardiomyopathy.
Abstract:
Cardiomyopathy is a major complication of thalassemia, yet the precise underlying molecular mechanisms remain unclear. We examined whether altered lipid metabolism is an early driving factor in the development of cardiomyopathy using the Th3/+ mouse model of thalassemia. At age 20 weeks, male and female Th3/+ mice manifested anemia and iron overload; however, only males displayed metabolic defects and altered cardiac function. Untargeted lipidomics indicated that the circulating levels of 35 lipid species were significantly altered in Th3/+ mice compared to wild-type controls: triglycerides (TGs) with saturated fatty acids (FAs; TG42:0 and TG44:0) were elevated, while TGs with unsaturated FAs (TG(18:2_20:5_18:2 and TG54:8)) were reduced. Similarly, phosphatidylcholines (PCs) with long chain FAs (palmitic (16:0) or oleic (18:1)) were increased, while PCs with polyunsaturated FAs decreased. Circulating PC(16:0_14:0), GlcCer(d18:1/24:0) correlated significantly with iron overload and cardiac hypertrophy. 16S rRNA gene profiling revealed alterations in the intestinal microbiota of Th3/+ mice. Differentially abundant bacterial genera correlated with PC(39:6), PC(18:1_22:6), GlcCer(d18:1/24:1) and CE(14:0). These results provide new knowledge on perturbations in lipid metabolism and the gut microbiota of Th3/+ mice and identify specific factors which may represent early biomarkers or therapeutic targets to prevent development of cardiomyopathy in β-thalassemia.
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