- •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.
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.
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.
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.
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.
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- The monocarboxylate transporter family–structure and functional characterization.IUBMB Life. 2012; 64: 1-9
- Monocarboxylate transporters (SLC16): function, regulation, and role in health and disease.Pharmacol Rev. 2020; 72: 466-485
- An overview of MCT1 and MCT4 in GBM: small molecule transporters with large implications.Am J Cancer Res. 2018; 8: 1967-1976
- Activity of the monocarboxylate transporter 1 inhibitor AZD3965 in small cell lung cancer.ClinCancer Res. 2014; 20: 926-937
- In vivo anticancer activity of AZD3965: a systematic review.Molecules. 2021; 27
- Monocarboxylate transporter 4 inhibition potentiates hepatocellular carcinoma immunotherapy through enhancing T cell infiltration and immune attack.Hepatology. 2022;
- Oligodendroglia metabolically support axons and contribute to neurodegeneration.Nature. 2012; 487: 443-448
- The science and translation of lactate shuttle theory.Cell Metab. 2018; 27: 757-785
- The lactate shuttle during exercise and recovery.Med Sci Sports Exerc. 1986; 18: 360-368
- Resistance to diet-induced obesity and associated metabolic perturbations in haploinsufficient monocarboxylate transporter 1 mice.PLoS One. 2013; 8e82505
- Lactate is a key mediator that links obesity to insulin resistance via modulating cytokine production from adipose tissue.Diabetes. 2022; 71: 637-652
- The hepatic monocarboxylate transporter 1 (MCT1) contributes to the regulation of food anticipation in mice.Front Physiol. 2021; 12665476
- Hepatic PPARalpha function is controlled by polyubiquitination and proteasome-mediated degradation through the coordinated actions of PAQR3 and HUWE1.Hepatology. 2018; 68: 289-303
- Metabolic regulation of gene expression by histone lactylation.Nature. 2019; 574: 575-580
- Sex hormones regulate rat hepatic monocarboxylate transporter expression and membrane trafficking.JPharmPharmSci. 2017; 20: 435-444
- Serine catabolism generates liver NADPH and supports hepatic lipogenesis.NatMetab. 2021; 3: 1608-1620
- Lactate kinetics in human tissues at rest and during exercise.Acta Physiol (Oxf). 2010; 199: 499-508
- Hepatic oxygen and lactate extraction during stagnant hypoxia.J Appl Physiol (1985). 1991; 70: 186-193
- Nonalcoholic steatohepatitis: the role of peroxisome proliferator-activated receptors.Nat Rev Gastroenterol Hepatol. 2021; 18: 24-39
Accepted: March 13, 2023
Received: November 15, 2022
Publication stageIn Press Journal Pre-Proof
© 2023 Published by Elsevier Inc.