A novel type hypertriglyceridemia observed in FLS mice

Area of Science:

• Genetics
• Biochemistry
• Metabolic Disorders

Background:

• Fatty liver Shionogi (FLS) mice display inherent hypertriglyceridemia.
• Apolipoprotein C-II (apoC-II) administration temporarily alleviates hypertriglyceridemia in FLS mice.
• Lipoprotein lipase (LPL) and apoC-II are crucial for very-low-density lipoprotein (VLDL) metabolism.

Purpose of the Study:

• To investigate the genetic basis of hypertriglyceridemia in FLS mice.
• To identify the specific genetic factor responsible for the observed lipid metabolism disorder.
• To determine the inheritance pattern and chromosomal location of the causative gene.

Main Methods:

• Measurement of plasma triglyceride (TG) and total cholesterol levels.
• Assay of lipoprotein lipase (LPL) activity.
• Analysis of lipoprotein profiles using agarose gel electrophoresis and fast protein liquid chromatography (FPLC).
• Cross-breeding experiments to determine genetic background.
• Determination of cDNA sequences for apoC-II and apoC-III.
• Microsatellite analysis for gene mapping.

Main Results:

• FLS mice predominantly exhibit prealpha-lipoprotein in plasma.
• LPL activity in FLS mice is comparable to control C57/BL6J mice.
• Administration of purified apoC-II provides transient relief from hypertriglyceridemia.
• Prealpha-lipoproteinemia follows an autosomal recessive inheritance pattern.
• Apolipoprotein C-III (apoC-III) is implicated as a causal factor, mapping to chromosome 9.
• Excess apoC-III attenuates LPL activity both in vivo and in vitro.

Conclusions:

• Apolipoprotein C-III (apoC-III) is identified as a strong candidate gene responsible for the unique hypertriglyceridemia in FLS mice.
• The excessive production or altered function of apoC-III likely impairs LPL activity, leading to hypertriglyceridemia.
• Understanding this genetic mechanism provides insights into VLDL metabolism and potential therapeutic targets for hypertriglyceridemia.