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Updated: Jul 10, 2026
Cell Type-specific Gene Expression Profiling in the Mouse Liver
Published on: September 17, 2019
Gene expression profiling in livers of mice after acute inhibition of beta-oxidation
Feike R van der Leij1, Vincent W Bloks, Aldo Grefhorst
1Center for Liver, Digestive, and Metabolic Diseases, Laboratory of Pediatrics, University Medical Center Groningen, University of Groningen, CMCV, Groningen, The Netherlands.
Abstract:
Inborn errors of mitochondrial beta-oxidation cause ectopic fat accumulation, particularly in the liver. Fatty liver is associated with insulin resistance and predisposes to hepatic fibrosis. The factors underlying the pathophysiological consequences of hepatic fat accumulation have remained poorly defined. Gene expression profiling in a model of acute fatty liver disease induced by blocking long-chain fatty acid beta-oxidation was performed to study the early effects of steatosis on the transcriptome. Tetradecylglycidic acid (TDGA) was used to irreversibly inhibit carnitine palmitoyltransferase 1, a key enzyme in the control of mitochondrial beta-oxidation. TDGA treatment induced massive microvesicular hepatic steatosis within a 12-h time frame in male C57BL6/J mice. Increased hepatic long-chain acyl-CoA content, particularly of C16:0, C16:1 and C18:1, was associated with profound effects on the transcriptome as revealed by unbiased gene expression profiling and quantitative real-time PCR. The results indicate drastic changes in the expression of genes encoding proteins involved in lipid, carbohydrate, and amino acid metabolism. Pathway analysis identified transcription factors and coregulators such as hepatocyte nuclear factor 4 (HNF4), peroxisome proliferator-activated receptor-alpha (PPAR-alpha), and PPAR gamma coactivator 1alpha (PGC-1alpha ) as key players in these metabolic adaptations. Apoptotic and profibrotic responses were also affected. Surprisingly, a strong reduction in the expression of genes involved in hepatic bile salt metabolism and transport was observed. Therefore, this transcriptome analysis opens new avenues for research.
Insights
Inborn errors in mitochondrial beta-oxidation cause fatty liver disease. This study reveals how blocking this process drastically alters liver gene expression, impacting metabolism and leading to potential fibrosis.
Area of Science:
- Biochemistry
- Molecular Biology
- Hepatology
Background:
- Inborn errors of mitochondrial beta-oxidation lead to ectopic fat accumulation, particularly in the liver.
- Fatty liver is linked to insulin resistance and hepatic fibrosis, but underlying factors are poorly understood.
Purpose of the Study:
- To investigate the early transcriptomic effects of steatosis (fatty liver) induced by inhibiting mitochondrial beta-oxidation.
Main Methods:
- Utilized Tetradecylglycidic acid (TDGA) to inhibit carnitine palmitoyltransferase 1, inducing acute hepatic steatosis in mice.
- Performed unbiased gene expression profiling and quantitative real-time PCR to analyze transcriptomic changes.
Main Results:
- TDGA treatment caused massive microvesicular hepatic steatosis and increased hepatic long-chain acyl-CoA content.
- Significant alterations were observed in genes regulating lipid, carbohydrate, and amino acid metabolism.
- Key transcription factors (HNF4, PPAR-alpha, PGC-1alpha) were identified as central to metabolic adaptations; apoptotic and profibrotic responses were affected.
- A surprising reduction in genes involved in hepatic bile salt metabolism and transport was noted.
Conclusions:
- Acute hepatic steatosis profoundly impacts the liver transcriptome, affecting multiple metabolic pathways.
- Transcription factors like HNF4, PPAR-alpha, and PGC-1alpha play crucial roles in the adaptive response to steatosis.
- The study highlights novel effects on bile salt metabolism and opens new research directions for fatty liver disease.
