LGR4 acts as a link between the peripheral circadian clock and lipid metabolism in liver

Dec 20, 2013Journal of molecular endocrinology

LGR4 connects the body's daily rhythm to fat processing in the liver

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Abstract

Lgr4 homozygous mutant mice exhibited alterations in the rhythms of respiratory exchange ratio and impaired plasma triglyceride rhythms.

Altered respiratory exchange ratio rhythms were observed in Lgr4 homozygous mutant (Lgr4(m/m)) mice.
Impaired plasma triglyceride rhythms were found in Lgr4(m/m) mice, indicating a disruption in lipid metabolism.
Cholesterol levels were lower in Lgr4(m/m) mice, despite no significant changes in plasma cholesterol rhythms.
Lgr4 expression in liver tissue and primary hepatocytes showed circadian rhythms, suggesting a link to metabolic regulation.
The diurnal expression pattern of the Mttp gene, important for plasma lipid levels, was impaired in Lgr4(m/m) mice.

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The circadian clock plays an important role in the liver by regulating the major aspects of energy metabolism. Currently, it is assumed that the circadian clock regulates metabolism mostly by regulating the expression of liver enzymes at the transcriptional level, but the underlying mechanism is not well understood. In this study, we showed that Lgr4 homozygous mutant (Lgr4(m/m)) mice showed alteration in the rhythms of the respiratory exchange ratio. We further detected impaired plasma triglyceride rhythms in Lgr4(m/m) mice. Although no significant changes in plasma cholesterol rhythms were observed in the Lgr4(m/m) mice, their cholesterol levels were obviously lower. This phenotype was further confirmed in the context of ob/ob mice, in which lack of LGR4 dampened circadian rhythms of triglyceride. We next demonstrated that Lgr4 expression exhibited circadian rhythms in the liver tissue and primary hepatocytes in mice, but we did not detect changes in the expression levels or circadian rhythms of classic clock genes, such as Clock, Bmal1 (Arntl), Pers, Rev-erbs, and Crys, in Lgr4(m/m) mice compared with their littermates. Among the genes related to the lipid metabolism, we found that the diurnal expression pattern of the Mttp gene, which plays an important role in the regulation of plasma lipid levels, was impaired in Lgr4(m/m) mice and primary Lgr4(m/m) hepatocytes. Taken together, our results demonstrate that LGR4 plays an important role in the regulation of plasma lipid rhythms, partially through regulating the expression of microsomal triglyceride transfer protein. These data provide a possible link between the peripheral circadian clock and lipid metabolism.

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LGR4 acts as a link between the peripheral circadian clock and lipid metabolism in liver

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