Research Article Details
| Article ID: | A15104 |
| PMID: | 29092796 |
| Source: | Mol Metab |
| Title: | AMPK activation caused by reduced liver lactate metabolism protects against hepatic steatosis in MCT1 haploinsufficient mice. |
| Abstract: | OBJECTIVE: Hepatic steatosis is the first step leading to non-alcoholic fatty liver disease, which represents a major complication of obesity. Here, we show that MCT1 haploinsufficient mice resist to hepatic steatosis development when fed a high fat diet. They exhibit a reduced hepatic capacity to metabolize monocarboxylates such as lactate compared to wildtype mice. METHODS: To understand how this resistance to steatosis develops, we used HFD fed wildtype mice with hepatic steatosis and MCT1 haploinsufficient mice to study hepatic metabolism. RESULTS: AMPK is constitutively activated in the liver of MCT1 haploinsufficient mice, leading to an inactivation of SREBP1. Therefore, expression of key transcription factors for lipid metabolism, such as PPARα and γ, CHREB, or SREBP1 itself, as well as several enzymes including FAS and CPT1, was not upregulated in these mice when fed a high fat diet. It is proposed that reduced hepatic lactate metabolism is responsible for the protection against hepatic steatosis in MCT1 haploinsufficient mice via a constitutive activation of AMPK and repression of several major elements involved in hepatic lipid metabolism. CONCLUSION: Our results support a role of increased lactate uptake in hepatocytes during HFD that, in turn, induce a metabolic shift stimulating SREBP1 activity and lipid accumulation. |
| DOI: | 10.1016/j.molmet.2017.10.005 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S02 | Enhance lipid metabolism | triglyceride-lowering; lipid tolerance; lipid metabolism | 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitor; Decreases intestinal cholesterol absorption; FXR agonist; ACC inhibitor; FAS inhibitor; DGAT2 inhibitor; SCD-1 inhibitor | Atorvastatin; Ezetimibe; Obeticholic Acid; GS-9674; GS-0976; TVB-2640; IONIS-DGAT2rx; Aramchol; | Details |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name | |
|---|---|---|---|---|---|---|---|
| T01 | 5'-AMP-activated protein kinase subunit beta-1 | PRKAB1 | activator | Kinase | Q9Y478 | AAKB1_HUMAN | Details |
| T10 | Caspase-1 | CASP1 | inhibitor | Enzyme | P29466 | CASP1_HUMAN | Details |
| T18 | Acetyl-CoA carboxylase 1 | ACACA | inhibitor | Enzyme | Q13085 | ACACA_HUMAN | Details |
| T20 | Fatty acid synthase | FASN | inhibitor | Enzyme | P49327 | FAS_HUMAN | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I14 | 9970 | Obesity | An overnutrition that is characterized by excess body fat, traditionally defined as an elevated ratio of weight to height (specifically 30 kilograms per meter squared), has_material_basis_in a multifactorial etiology related to excess nutrition intake, decreased caloric utilization, and genetic susceptibility, and possibly medications and certain disorders of metabolism, endocrine function, and mental illness. https://en.wikipedia.org/wiki/Obesity | disease of metabolism/acquired metabolic disease/ nutrition disease/overnutrition | Details |