title: Palmitate Inhibits SIRT1-Dependent BMAL1/CLOCK Interaction and Disrupts Circadian Gene Oscillations in Hepatocytes.
abstract: Elevated levels of serum saturated fatty acid palmitate have been shown to promote insulin resistance, increase cellular ROS production, and trigger cell apoptosis in hepatocytes during the development of obesity. However, it remains unclear whether palmitate directly impacts the circadian clock in hepatocytes, which coordinates nutritional inputs and hormonal signaling with downstream metabolic outputs. Here we presented evidence that the molecular clock is a novel target of palmitate in hepatocytes. Palmitate exposure at low dose inhibits the molecular clock activity and suppresses the cyclic expression of circadian targets including Dbp, Nr1d1 and Per2 in hepatocytes. Palmitate treatment does not seem to alter localization or reduce protein expression of BMAL1 and CLOCK, the two core components of the molecular clock in hepatocytes. Instead, palmitate destabilizes the protein-protein interaction between BMAL1-CLOCK in a dose and time-dependent manner. Furthermore, we showed that SIRT1 activators could reverse the inhibitory action of palmitate on BMAL1-CLOCK interaction and the clock gene expression, whereas inhibitors of NAD synthesis mimic the palmitate effects on the clock function. In summary, our findings demonstrated that palmitate inhibits the clock function by suppressing SIRT1 function in hepatocytes.
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Xin
authors.initials: X
authors.lastname: Tong
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Deqiang
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Blake
authors.initials: B
authors.lastname: Arthurs
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Pei
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Leigh
authors.initials: L
authors.lastname: Durudogan
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Neil
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Lei
authors.initials: L
authors.lastname: Yin
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D010168:Palmitates / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D010168:Palmitates; D012333:RNA, Messenger; D056926:CLOCK Proteins; C538944:Clock protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1