Abstract
CREB3L3 is involved in fatty acid oxidation and ketogenesis in a mutual manner with PPARα. To evaluate relative contribution, a combination of knockout and transgenic mice was investigated. On a ketogenic-diet (KD) that highlights capability of hepatic ketogenesis, Creb3l3-/- mice exhibited reduction of expression of genes for fatty oxidation and ketogenesis comparable to Ppara-/- mice. Most of the genes were further suppressed in double knockout mice indicating independent contribution of hepatic CREB3L3. During fasting, dependency of ketogenesis on CREB3L3 is lesser extents than Ppara-/- mice suggesting importance of adipose PPARα for supply of FFA and hyperlipidemia in Creb3l3-/- mice. In conclusion CREB3L3 plays a crucial role in hepatic adaptation to energy starvation via two pathways: direct related gene regulation and an auto-loop activation of PPARα. Furthermore, as KD-fed Creb3l3-/- mice exhibited severe fatty liver, activating inflammation, CREB3L3 could be a therapeutic target for NAFLD.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenoviridae / genetics
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Animals
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Blood Glucose / analysis
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Carnitine O-Palmitoyltransferase / chemistry
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Carnitine O-Palmitoyltransferase / genetics
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Carnitine O-Palmitoyltransferase / metabolism
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Cell Line, Tumor
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Cyclic AMP Response Element-Binding Protein / deficiency
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Cyclic AMP Response Element-Binding Protein / genetics*
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Diet, Ketogenic
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Energy Metabolism
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Fatty Acids / chemistry*
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Fatty Acids / metabolism
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Fatty Liver / etiology
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Fatty Liver / metabolism
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Fibroblast Growth Factors / blood
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Gene Expression
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Lipid Peroxidation
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Liver / metabolism
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Liver / pathology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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PPAR alpha / deficiency
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PPAR alpha / genetics*
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Plasmids / genetics
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Plasmids / metabolism
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Promoter Regions, Genetic
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RNA, Messenger / metabolism
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Triglycerides / blood
Substances
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Blood Glucose
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Creb3l3 protein, mouse
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Cyclic AMP Response Element-Binding Protein
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Fatty Acids
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PPAR alpha
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RNA, Messenger
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Triglycerides
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fibroblast growth factor 21
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Fibroblast Growth Factors
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CPT1B protein, mouse
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Carnitine O-Palmitoyltransferase