Defining the Independence of the Liver Circadian Clock

Abstract

SUMMARY Mammals rely on a network of circadian clocks to control daily systemic metabolism and physiology. The central pacemaker in the suprachiasmatic nucleus (SCN) is considered hierarchically dominant over peripheral clocks, whose degree of independence, or tissue level autonomy, has never been ascertained in vivo. Using arrhythmic Bmal1-null mice, we generated animals with reconstituted circadian expression of BMAL1 exclusively in the liver (Liver-RE). High-throughput transcriptomics and metabolomics show that the liver has independent circadian functions, specific for metabolic processes such as the NAD+ salvage pathway and glycogen turnover. However, although BMAL1 occupies chromatin at most genomic targets in Liver-RE mice, circadian expression is restricted to ~ 10% of normally rhythmic transcripts. Finally, rhythmic clock gene expression is lost in Liver-RE mice under constant darkness. Hence, full circadian function in the liver depends on signals emanating from other clocks and light contributes to tissue-autonomous clock function.

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

“…A previous study has demonstrated that expression levels of clock genes including PER1 and PER2 differ before and after feeding as well as in different tissues, such as the hypothalamus, the skeletal muscle, and the liver, in swine . Koronowski et al have generated transgenic mice, which have a stop cassette inserted between exon 5 and 6 of BMAL1 resulting in global BMAL1 knockout phenotypes . The stop cassette was flanked by loxP sites and crossing those global BMAL1 −/− mice with mice that express Cre recombinase under the control of α‐fetoprotein enhancer ( Alfp ‐Cre mice) allowed the removal of the stop cassette specifically in Alfp‐positive hepatic cells .…”

“…Cre expression is observed selectively in hepatocytes and cholangiocytes in Alfp ‐Cre mice . As a result, crossed mice expressed BMAL1 only in the liver (hepatocytes and cholangiocytes) . Global BMAL1 −/− mice lost circadian rhythms and expressions, but mice with hepatic BMAL1 expression had rhythmic circadian expressions and metabolisms in the liver without BMAL1 expression and circadian rhythms in the brain and other organs .…”

“…As a result, crossed mice expressed BMAL1 only in the liver (hepatocytes and cholangiocytes) . Global BMAL1 −/− mice lost circadian rhythms and expressions, but mice with hepatic BMAL1 expression had rhythmic circadian expressions and metabolisms in the liver without BMAL1 expression and circadian rhythms in the brain and other organs . This liver‐specific rhythm was dependent on light‐dark cycle, indicating that the liver may have independent circadian rhythms and functions .…”

“…Global BMAL1 −/− mice lost circadian rhythms and expressions, but mice with hepatic BMAL1 expression had rhythmic circadian expressions and metabolisms in the liver without BMAL1 expression and circadian rhythms in the brain and other organs . This liver‐specific rhythm was dependent on light‐dark cycle, indicating that the liver may have independent circadian rhythms and functions . Since circadian rhythms regulate various physiological events throughout the body, the association of disrupted circadian rhythms with human disorders including liver diseases has been suggested …”

“…5 The stop cassette was flanked by loxP sites and crossing those global BMAL1 −/− mice with mice that express Cre recombinase under the control of α-fetoprotein enhancer (Alfp-Cre mice) allowed the removal of the stop cassette specifically in Alfp-positive hepatic cells. 5 Cre expression is observed selectively in hepatocytes and cholangiocytes in Alfp-Cre mice. 6 As a result, crossed mice expressed BMAL1 only in the liver (hepatocytes and cholangiocytes).…”