Abstract
Transient hepatic steatosis upon liver resection supposes functional relationships between lipid metabolism and liver regeneration. Repin1 has been suggested as candidate gene for obesity and dyslipidemia by regulating key genes of lipid metabolism and lipid storage. Herein, we characterized the regenerative potential of mice with a hepatic deletion of Repin1 (LRep1−/−) after partial hepatectomy (PH) in order to determine the functional significance of Repin1 in liver regeneration. Lipid dynamics and the regenerative response were analyzed at various time points after PH. Hepatic Repin1 deficiency causes a significantly decreased transient hepatic lipid accumulation. Defects in lipid uptake, as analyzed by decreased expression of the fatty acid transporter Cd36 and Fatp5, may contribute to attenuated and shifted lipid accumulation, accompanied by altered extent and chronological sequence of liver cell proliferation in LRep1−/− mice. In vitro steatosis experiments with primary hepatocytes also revealed attenuated lipid accumulation and occurrence of smaller lipid droplets in Repin1-deficient cells, while no direct effect on proliferation in HepG2 cells was observed. Based on these results, we propose that hepatocellular Repin1 might be of functional significance for early accumulation of lipids in hepatocytes after PH, facilitating efficient progression of liver regeneration.
Highlights
Identified as a candidate gene in the quantitative trait locus for facets of the metabolic syndrome in subcongenic rat strains[1], further investigations showed that expression of the Replication initiator 1 (Repin1) in the liver and adipose tissue is significantly associated with obesity and dyslipidemia[2,3,4,5]
Altered regulation of metabolic genes and pathways involved in insulin signaling, lipid and glucose metabolism is functionally important for the initiation of regeneration upon hepatic insufficiency
The importance of Repin[1] for fatty acid (FA) uptake in adipocytes has been implied previously[2,4,6,31] which is in line with our data, as hepatic deficiency of Repin[1] causes reduced lipid content in hepatocytes during the early phase of liver regeneration
Summary
Identified as a candidate gene in the quantitative trait locus for facets of the metabolic syndrome in subcongenic rat strains[1], further investigations showed that expression of the Replication initiator 1 (Repin1) in the liver and adipose tissue is significantly associated with obesity and dyslipidemia[2,3,4,5]. Ruschke et al.[2] showed that Repin[1] in adipocytes regulates the expression of genes involved in adipogenesis, lipid droplet formation and fusion as well as glucose and fatty acid (FA) transport. Thereby, transient accumulation of lipids in the regenerating liver is a well-known phenomenon and appears to be essential for adequate liver regeneration after hepatic resection[7,8,9,10] It might serve as energy source for subsequent metabolic events associated with the regenerative process and reconstruction of cell membranes[11].
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