Highlights
- •Hepatic deletion of Slc16a1 aggravates HFD-induced obesity in female mice, but not in male mice.
- •Deficiency of MCT1 in the liver aggravates HFD-induced hepatic steatosis in both female and male mice.
- •MCT1 mainly mediates the efflux of lactate in hepatocytes.
- •MCT1 deletion enhances polyubiquitination and degradation of PPARα, leading to reduced expression of FAO-related genes.
Abstract
Background
The monocarboxylate transporter 1 (MCT1) is a member of the MCT family and is implicated
in the transport of lactate and a few other monocarboxylates across the cell membrane.
How hepatic MCT1 regulates the metabolic functions of the body is currently unknown.
Methods
The functions of hepatic MCT1 on metabolism were analyzed using a mouse model with
liver-specific deletion of Slc16a1 that encodes MCT1. Obesity and hepatosteatosis of the mice were induced by high fat
diet (HFD). The function of MCT1 on lactate transport was analyzed by measuring lactate
level in hepatocytes and mouse liver. Degradation and polyubiquitination of PPARα
protein were investigated by biochemical methods.
Results
Hepatic deletion of Slc16a1 aggravated high-fat diet (HFD)-induced obesity in female mice, but not in male mice.
However, the increased adiposity in Slc16a1-deleted mice was not associated with obvious reductions in metabolic rate and activity.
The lactate level of the liver was significantly increased by Slc16a1 deletion in the female mice under HFD condition, suggesting that MCT1 mainly mediated
the efflux of lactate in hepatocytes. Deficiency of MCT1 in the liver aggravated HFD-induced
hepatic steatosis in both female and male mice. Mechanistically, deletion of Slc16a1 was associated with reduced expressions of genes involved in fatty acid oxidation
(FAO) in the liver. The degradation rate and polyubiquitination of PPARα protein were
enhanced by Slc16a1 deletion. Blocking the MCT1 function elevated the interaction of PPARα with an E3
ubiquitin ligase HUWE1.
Conclusions
Our findings suggested that the enhanced polyubiquitination and degradation of PPARα
upon Slc16a1 deletion likely contributes to the reduced expression of FAO-related genes and aggravation
of HFD-induced hepatic steatosis.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Accepted:
March 13,
2023
Received:
November 15,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2023 Published by Elsevier Inc.
