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Hepatic PKA inhibition accelerates the lipid accumulation in liver
Jining Yang1, Xiaoying Zhang2, Long Yi1
11Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, People's Republic of China.
Background/Aims:
Liver lipid accumulation induced by high-fat diet (HFD) is an early onset process of non-alcoholic fatty liver diseases (NAFLD). Protein kinase A (PKA) is known to be involved in hepatic lipid metabolism. However, the role of PKA in NAFLD has not been well tested in vivo due to the lack of optimal PKA deficient mouse model.
Methods:
A novel PKA-specific inhibitor gene was conditionally overexpressed in mouse (PKAi mouse) liver using LoxP/Cre system. PKA activity in the liver extract was measured with a commercial assay kit. The PKAi and control mice of 8-week age, were subjected to HFD or chow diet (CD) for 2 months. Body weight, liver index, and triglyceride in the liver were measured. RNA sequencing was performed for the liver tissues and analyzed with Gene Ontology (GO) and pathway enrichment.
Results:
PKAi-GFP protein was overexpressed in the liver and the PKA activation was significantly inhibited in the liver of PKAi mouse. When fed with CD, RNA sequencing revealed 56 up-regulated and 51 down-regulated genes in PKAi mice compared with control mice, which were mainly involved in lipid metabolism though no significant differences in the body weight, liver index, triglyceride accumulation were observed between PKAi and control mice. However, when fed with HFD for 2 months, the liver was enlarged more, and the accumulation of triglyceride in the liver was more severe in PKAi mice. When comparing the transcriptomes of CD-fed and HFD-fed control mice, GO enrichment showed that the genes down-regulated by HFD were mainly enriched in immune-related GO terms, and up-regulated genes were enriched in metabolism. When comparing the transcriptomes of CD-fed and HFD-fed PKAi mice, GO analysis showed that the down-regulated genes were enriched in metabolism, while the up-regulated genes were clustered in ER stress-related pathways. When comparing HFD-fed PKAi and HFD-fed control mice, the genes with lower expression level in PKAi mice were enriched in the lipoprotein synthesis, which might explain that more TG is accumulated in PKAi liver after HFD feeding.
Conclusions:
Reduced PKA activity could be a factor promoting the TG accumulation in the liver and the development of NAFLD.
Insights
Reduced protein kinase A (PKA) activity exacerbates high-fat diet-induced liver triglyceride accumulation, suggesting PKA plays a protective role in non-alcoholic fatty liver disease (NAFLD) development.
Area of Science:
- Hepatology
- Molecular Biology
- Metabolic Diseases
Background:
- Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive liver lipid accumulation, often initiated by high-fat diets (HFD).
- Protein kinase A (PKA) is implicated in hepatic lipid metabolism, but its in vivo role in NAFLD pathogenesis remains unclear due to a lack of suitable models.
Purpose of the Study:
- To investigate the in vivo role of PKA in hepatic lipid metabolism and NAFLD development.
- To establish and utilize a novel mouse model with liver-specific PKA inhibition.
Main Methods:
- Developed a conditional PKA inhibitor (PKAi) mouse model using the LoxP/Cre system for liver-specific PKA knockdown.
- Subjected PKAi and control mice to 2 months of either HFD or chow diet (CD).
- Assessed liver triglyceride levels, body weight, liver index, and performed RNA sequencing with Gene Ontology (GO) and pathway enrichment analysis.
Main Results:
- PKA inhibition in the liver was confirmed in PKAi mice.
- While chow diet feeding showed minor metabolic gene alterations, HFD feeding in PKAi mice led to significantly increased liver enlargement and triglyceride accumulation compared to controls.
- Transcriptomic analysis revealed that reduced PKA activity under HFD conditions was associated with downregulated genes in lipoprotein synthesis and upregulated genes in ER stress pathways.
Conclusions:
- Reduced hepatic PKA activity promotes triglyceride accumulation in the liver.
- PKA may act as a protective factor against the development and progression of NAFLD.
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