Methionine adenosyltransferase 1A gene deletion disrupts hepatic very low-density lipoprotein assembly in mice

Aug 13, 2011Hepatology (Baltimore, Md.)

Deleting a key gene disrupts liver fat particle formation in mice

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Abstract

MAT1A is required for normal VLDL assembly and plasma lipid homeostasis in mice.

MAT1A deletion in 3-month-old knockout mice led to decreased mobilization of triglyceride stores and impaired triglyceride secretion in VLDL.
In 3-KO mice, there was an increase in the secretion of VLDL-apolipoprotein B, resulting in small, lipid-poor VLDL particles.
Administration of S-adenosylmethionine (SAMe) to 3-KO mice for 7 days restored crucial processes in VLDL assembly.
In 8-month-old MAT1A-knockout mice, triglyceride accumulation and altered lipid ratios were observed, indicating impaired lipid handling.
MAT1A deletion also resulted in altered plasma lipid homeostasis, increasing lipid transport in low-density lipoprotein and decreasing it in high-density lipoprotein subclasses.

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UNLABELLED: Very low-density lipoprotein (VLDL) secretion provides a mechanism to export triglycerides (TG) from the liver to peripheral tissues, maintaining lipid homeostasis. In nonalcoholic fatty liver disease (NAFLD), VLDL secretion disturbances are unclear. Methionine adenosyltransferase (MAT) is responsible for S-adenosylmethionine (SAMe) synthesis and MAT I and III are the products of the MAT1A gene. Deficient MAT I and III activities and SAMe content in the liver have been associated with NAFLD, but whether MAT1A is required for normal VLDL assembly remains unknown. We investigated the role of MAT1A on VLDL assembly in two metabolic contexts: in 3-month-old MAT1A-knockout mice (3-KO), with no signs of liver injury, and in 8-month-old MAT1A-knockout mice (8-KO), harboring nonalcoholic steatohepatitis. In 3-KO mouse liver, there is a potent effect of MAT1A deletion on lipid handling, decreasing mobilization of TG stores, TG secretion in VLDL and phosphatidylcholine synthesis via phosphatidylethanolamine N-methyltransferase. MAT1A deletion also increased VLDL-apolipoprotein B secretion, leading to small, lipid-poor VLDL particles. Administration of SAMe to 3-KO mice for 7 days recovered crucial altered processes in VLDL assembly and features of the secreted lipoproteins. The unfolded protein response was activated in 8-KO mouse liver, in which TG accumulated and the phosphatidylcholine-to-phosphatidylethanolamine ratio was reduced in the endoplasmic reticulum, whereas secretion of TG and apolipoprotein B in VLDL was increased and the VLDL physical characteristics resembled that in 3-KO mice. MAT1A deletion also altered plasma lipid homeostasis, with an increase in lipid transport in low-density lipoprotein subclasses and decrease in high-density lipoprotein subclasses.

CONCLUSION: MAT1A is required for normal VLDL assembly and plasma lipid homeostasis in mice. Impaired VLDL synthesis, mainly due to SAMe deficiency, contributes to NAFLD development in MAT1A-KO mice.

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