Increased peripheral lipid clearance in an animal model of amyotrophic lateral sclerosis

TL;DR

This study reveals that in an ALS mouse model, peripheral lipid clearance is increased, and a high-fat diet can correct metabolic defects, potentially explaining its neuroprotective effects.

Contribution

It demonstrates that lipid metabolism is altered in ALS mice, with increased peripheral clearance, and shows dietary lipids can restore normal metabolism and confer neuroprotection.

Findings

Peripheral triglyceride clearance is markedly increased in ALS mice.

High-fat diet corrects lipid metabolism defects and extends lifespan.

Energy metabolism shifts toward increased peripheral lipid use in ALS model.

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common adult motor neuron disease, causing motor neuron degeneration, muscle atrophy, paralysis, and death. Despite this degenerative process, a stable hypermetabolic state has been observed in a large subset of patients. Mice expressing a mutant form of Cu/Zn-superoxide dismutase (mSOD1 mice) constitute an animal model of ALS that, like patients, exhibits unexpectedly increased energy expenditure. Counterbalancing for this increase with a high-fat diet extends lifespan and prevents motor neuron loss. Here, we investigated whether lipid metabolism is defective in this animal model. Hepatic lipid metabolism was roughly normal, whereas gastrointestinal absorption of lipids as well as peripheral clearance of triglyceride-rich lipoproteins were markedly increased, leading to decreased postprandial lipidemia. This defect was corrected by the high-fat regimen that typically induces neuroprotection in these animals. Together, our findings show that energy metabolism in mSOD1 mice shifts toward an increase in the peripheral use of lipids. This metabolic shift probably accounts for the protective effect of dietary lipids in this model.