Clock represses preadipocytes adipogenesis via GILZ.

Adiposity is a worldwide health threat that needs to be prevented. Circadian gene Clock (circadian locomotor output cycles kaput) is closely correlated to adiposity; for example, weight gain, adipocytes size expansion, and serum lipid level rise in ClockΔ19 mice compared to C57BL/6J mice. However, the precise role of Clock during adipogenic differentiation is unknown. Herein, the circadian gene Clock is shown to regulate adipogenesis mediated by GILZ. Clock-mediated attenuation and upregulation influenced lipid synthesis and affected the levels of adipogenic transcriptional factors, C/EBP-ß, C/EBP-α, PPAR-γ, and FABP4, both in vivo and in vitro (primary adipose-derived stromal cells and 3T3-L1 cells). Chromatin immunoprecipitation (ChIP) assay, reporter gene assay, and serum shock assay found that Clock transcriptionally regulated the glucocorticoid-induced leucine zipper (GILZ). Furthermore, GILZ attenuation could relieve the inhibitory effect of Clock on lipid synthesis and GILZ overexpression also reduced the promotion role of Clock attenuation in adipogenesis suggesting that Clock inhibits adipogenic differentiation of preadipocytes via GILZ. The current results demonstrate how circadian genes are likely to regulate adiposity, affecting the adipogenic differentiation process, as well as, increasing the fat cells number. Therefore, this study may provide novel insights into the underlying mechanism explaining the correlation between Clock mutation and adiposity.

CLOCK promotes 3T3-L1 cell proliferation via Wnt signaling.

Circadian genes control most of the physiological functions including cell cycle. Cell proliferation is a critical factor in the differentiation of progenitor cells. However, the role of Clock gene in the regulation of cell cycle via wingless-type (Wnt) pathway and the relationship between Clock and adipogenesis are unclear. We found that the circadian locomotor output cycles kaput (Clock) regulated the proliferation and the adipogenesis of 3T3-L1 preadipocytes. We found that Clock attenuation inhibited the viability of 3T3-L1 preadipocytes in the cell counting kit 8. The expression of c-Myc and Cyclin D1 decreased dramatically in 3T3-L1 when Clock was silenced with short interfering RNA and was also decreased in fat tissue and adipose tissue-derived stem cells of Clock(Δ19) mice. Clock directly controls the expression of the components of Wnt signal transduction pathway, which was verified by serum shock, chromatin immunoprecipitation, Western blot, and quantitative real-time polymerase chain reaction (qRT-PCR). Furthermore, IWR-1, a Wnt signal pathway inhibitor, inhibited the cell cycle promotion by CLOCK, which was detected by cell viability assay, flow cytometry, and qRT-PCR. Therefore, CLOCK transcription control of Wnt signaling promotes cell cycle progression in 3T3-L1 preadipocytes. Clock inhibited the adipogenesis on day 2 in 3T3-L1 cells via Oil Red O staining and qRT-PCR detection and probably related to cellular differentiation. These data provide evidence that the circadian gene Clock regulates the proliferation of preadipocytes and affects adipogenesis. © 2016 IUBMB Life, 68(7):557-568, 2016.

Intermedin modulates hypoxic pulmonary vascular remodeling by inhibiting pulmonary artery smooth muscle cell proliferation.

BACKGROUND: Hypoxic pulmonary arterial hypertension (PAH) is a disabling disease with limited treatment options. Hypoxic pulmonary vascular remodeling is a major cause of hypoxic PAH. Pharmacological agents that can inhibit the remodeling process may have great therapeutic value. OBJECTIVE: To examine the effect of intermedin (IMD), a new calcitonin gene-related peptide family of peptide, on hypoxic pulmonary vascular remodeling. METHODS: Rats were exposed to normoxia or hypoxia (∼10% O(2)), or exposed to hypoxia and treated with IMD, administered by an implanted mini-osmotic pump (6.5 µg/rat/day), for 4 weeks. The effects of IMD infusion on the development of hypoxic PAH and right ventricle (RV) hypertrophy, on pulmonary vascular remodeling, on pulmonary artery smooth muscle cell (PASMC) proliferation and apoptosis, and on the activations of l-arginine nitric oxide (NO) pathway and endoplasmic reticulum stress apoptotic pathway were examined. RESULTS: Rats exposed to hypoxia developed PAH and RV hypertrophy. IMD treatment alleviated PAH and prevented RV hypertrophy. IMD inhibited hypoxic pulmonary vascular remodeling as indicated by reduced wall thickness and increased lumen diameter of pulmonary arterioles, and decreased muscularization of distal pulmonary vasculature in hypoxia-exposed rats. IMD treatment inhibited PASMC proliferation and promoted PASMC apoptosis. IMD treatment increased tissue level of constitutive NO synthase activity and tissue NO content in lungs, and enhanced l-arginine uptake into pulmonary vascular tissues. IMD treatment increased cellular levels of glucose-regulated protein (GRP) 78 and GRP94, two major markers of endoplasmic reticulum (ER) stress, and increased caspase-12 expression, the ER stress-specific caspase, in lungs and cultured PASMCs. CONCLUSIONS: These results demonstrate that IMD treatment attenuates hypoxic pulmonary vascular remodeling, and thereby hypoxic PAH mainly by inhibiting PASMC proliferation. Promotion of PASMC apoptosis may also contribute to the inhibitory effect of IMD. Activations l-arginine-NO pathway and of ER stress-specific apoptosis pathway could be the mechanisms mediating the anti-proliferative and pro-apoptotic effects of IMD.

RGS12 represses oral squamous cell carcinoma by driving M1 polarization of tumor-associated macrophages via controlling ciliary MYCBP2/KIF2A signaling.

Tumor-associated macrophages (TAMs) play crucial roles in tumor progression and immune responses. However, mechanisms of driving TAMs to antitumor function remain unknown. Here, transcriptome profiling analysis of human oral cancer tissues indicated that regulator of G protein signaling 12 (RGS12) regulates pathologic processes and immune-related pathways. Mice with RGS12 knockout in macrophages displayed decreased M1 TAMs in oral cancer tissues, and extensive proliferation and invasion of oral cancer cells. RGS12 increased the M1 macrophages with features of increased ciliated cell number and cilia length. Mechanistically, RGS12 associates with and activates MYC binding protein 2 (MYCBP2) to degrade the cilia protein kinesin family member 2A (KIF2A) in TAMs. Our results demonstrate that RGS12 is an essential oral cancer biomarker and regulator for immunosuppressive TAMs activation.

Regulator of G protein signaling 12 drives inflammatory arthritis by activating synovial fibroblasts through MYCBP2/KIF2A signaling.

Synovial fibroblasts are the active and aggressive drivers in the progression of arthritis, but the cellular and molecular mechanisms remain unknown. Here, our results showed that regulator of G protein signaling 12 (RGS12) maintained ciliogenesis in synovial fibroblasts, which is critical for the development of inflammatory arthritis. Deletion of RGS12 led to a significant decrease in ciliogenesis, adhesion, migration, and secretion of synovial fibroblasts. Mechanistically, RGS12 overexpression in synovial fibroblasts increased the length and number of cilia but decreased the protein level of kinesin family member 2A (KIF2A). The results of LC-MS analyses showed that RGS12 interacted with MYC binding protein 2 to enhance its ubiquitination activity, through which the KIF2A protein was degraded in synovial fibroblasts. Moreover, overexpression of KIF2A blocked the increases in cilia length and number. Mice with RGS12 deficiency or treatment of RGS12 shRNA nanoparticles significantly decreased the clinical score, paw swelling, synovitis, and cartilage destruction during inflammatory arthritis by inhibiting the activation of synovial fibroblasts. Therefore, this study provides evidence that RGS12 activates synovial fibroblasts' pathological function via promoting MCYBP2-mediated degradation of KIF2A and ciliogenesis. Our data suggest that RGS12 may be a potential drug target for the treatment of inflammatory arthritis.

Corrigendum to "Endothelial RGS12 governs angiogenesis in inflammatory arthritis by controlling cilia formation and elongation via MYCBP2 signaling" [Cell Insight 1 (2022) 100055].

[This corrects the article DOI: 10.1016/j.cellin.2022.100055.].

Diabetes impairs fracture healing through Foxo1 mediated disruption of ciliogenesis.

Foxo1 upregulation is linked to defective fracture healing under diabetic conditions. Previous studies demonstrated that diabetes upregulates Foxo1 expression and activation and diabetes impairs ciliogenesis resulting in defective fracture repair. However, the mechanism by which diabetes causes cilia loss during fracture healing remains elusive. We report here that streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM) dramatically increased Foxo1 expression in femoral fracture calluses, which thereby caused a significant decrease in the expression of IFT80 and primary cilia number. Ablation of Foxo1 in osteoblasts in OSXcretTAFoxo1f/f mice rescued IFT80 expression and ciliogenesis and restored bone formation and mechanical strength in diabetic fracture calluses. In vitro, advanced glycation end products (AGEs) impaired cilia formation in osteoblasts and reduced the production of a mineralizing matrix, which were rescued by Foxo1 deletion. Mechanistically, AGEs increased Foxo1 expression and transcriptional activity to inhibit IFT80 expression causing impaired cilia formation. Thus, our findings demonstrate that diabetes impairs fracture healing through Foxo1 mediated inhibition of ciliary IFT80 expression and primary cilia formation, resulting in impaired osteogenesis. Inhibition of Foxo1 and/or restoration of cilia formation has the potential to promote diabetes-impaired fracture healing.

Effect of Regulator of G Protein Signaling Proteins on Bone.

Regulator of G protein signaling (RGS) proteins are critical negative molecules of G protein-coupled receptor (GPCR) signaling, which mediates a variety of biological processes in bone homeostasis and diseases. The RGS proteins are divided into nine subfamilies with a conserved RGS domain which plays an important role in regulating the GTPase activity. Mutations of some RGS proteins change bone development and/or metabolism, causing osteopathy. In this review, we summarize the recent findings of RGS proteins in regulating osteoblasts, chondrocytes, and osteoclasts. We also highlight the impacts of RGS on bone development, bone remodeling, and bone-related diseases. Those studies demonstrate that RGS proteins might be potential drug targets for bone diseases.

Endothelial RGS12 governs angiogenesis in inflammatory arthritis by controlling cilia formation and elongation via MYCBP2 signaling.

Angiogenesis is the formation of new capillaries that plays an essential role in the pathogenesis of inflammatory arthritis. However, the cellular and molecular mechanisms remain unclear. Here, we provide the first evidence that regulator of G-protein signaling 12 (RGS12) promotes angiogenesis in inflammatory arthritis through governing ciliogenesis and cilia elongation in endothelial cells. The knockout of RGS12 inhibits the development of inflammatory arthritis with the reduction in clinical score, paw swelling, and angiogenesis. Mechanistically, RGS12 overexpression (OE) in endothelial cells increases cilia number and length, and thereby promotes cell migration and tube-like structure formation. The knockout of cilia marker protein Intraflagellar transport (IFT) 80 blocked the increase in cilia number and length caused by RGS12 OE. Moreover, the results from LC/MS and IP analysis showed that RGS12 is associated with cilia-related protein MYC binding protein 2 (MYCBP2), which enhances the phosphorylation of MYCBP2 to promote ciliogenesis in endothelial cells. These findings demonstrate that upregulation of RGS12 by inflammation enhances angiogenesis by promoting cilia formation and elongation via activation of MYCBP2 signaling during inflammatory arthritis pathogenesis.

Macrophage RGS12 contributes to osteoarthritis pathogenesis through enhancing the ubiquitination.

Ubiquitination has important functions in osteoarthritis (OA), yet the mechanism remains unclear. Here, we identify the regulator of G protein signaling 12 (RGS12) in macrophages, which promotes the association between ubiquitin and IκB during inflammation. We also find that RGS12 promotes the degradation of IκB through enhancing the ubiquitination whereas the process can be inhibited by MG132. Moreover, the increased ubiquitination further inhibits the expression of MTAP, which can indirectly activate the phosphorylation of IκB. Finally, due to the degradation of IκB, the NF-κB translocates into the nucleus and further promotes the gene expression of cytokines such as IL1ß, IL6, and TNFα during inflammation. Importantly, RGS12 deficiency prevents ubiquitination and inflammation in surgically or chemically induced OA. We conclude that the lack of RGS12 in macrophages interferes with the ubiquitination and degradation of IκB, thereby preventing inflammation and cartilage damage. Our results provide evidence for the relevance of RGS12 in promoting inflammation and regulating immune signaling.

Type II collagen-positive progenitors are important stem cells in controlling skeletal development and vascular formation.

Type II collagen-positive (Col2+) cells have been reported as skeletal stem cells (SSCs), but the contribution of Col2+ progenitors to skeletal development both prenatally and postnatally during aging remains unclear. To address this question, we generated new mouse models with ablation of Col2+ cells at either the embryonic or postnatal stages. The embryonic ablation of Col2+ progenitors resulted in the death of newborn mice due to a decrease in skeletal blood vessels, loss of all vertebral bones and absence of most other bones except part of the craniofacial bone, the clavicle bone and a small piece of the long bone and ribs, which suggested that intramembranous ossification is involved in long bone development but does not participate in spine development. The postnatal ablation of Col2+ cells resulted in mouse growth retardation and a collagenopathy phenotype. Lineage tracing experiments with embryonic or postnatal mice revealed that Col2+ progenitors occurred predominantly in the growth plate (GP) and articular cartilage, but a limited number of Col2+ cells were detected in the bone marrow. Moreover, the number and differentiation ability of Col2+ progenitors in the long bone and knee joints decreased with increasing age. The fate-mapping study further revealed Col2+ lineage cells contributed to, in addition to osteoblasts and chondrocytes, CD31+ blood vessels in both the calvarial bone and long bone. Specifically, almost all blood vessels in calvarial bone and 25.4% of blood vessels in long bone were Col2+ lineage cells. However, during fracture healing, 95.5% of CD31+ blood vessels in long bone were Col2+ lineage cells. In vitro studies further confirmed that Col2+ progenitors from calvarial bone and GP could form CD31+ vascular lumens. Thus, this study provides the first demonstration that intramembranous ossification is involved in long bone and rib development but not spine development. Col2+ progenitors contribute to CD31+ skeletal blood vessel formation, but the percentage differs between long bone and skull bone. The number and differentiation ability of Col2+ progenitors decreases with increasing age.

The Effect of IFT80 Deficiency in Osteocytes on Orthodontic Loading-Induced and Physiologic Bone Remodeling: In Vivo Study.

Osteocytes are the main mechanosensory cells during orthodontic and physiologic bone remodeling. However, the question of how osteocytes transmit mechanical stimuli to biological responses remains largely unanswered. Intraflagellar transport (IFT) proteins are important for the formation and function of cilia, which are proposed to be mechanical sensors in osteocytes. In particular, IFT80 is highly expressed in mouse skulls and essential for ciliogenesis. This study aims to investigate the short- and long-term effects of IFT80 deletion in osteocytes on orthodontic bone remodeling and physiological bone remodeling in response to masticatory force. We examined 10-week-old experimental DMP1 CRE+.IFT80f/f and littermate control DMP1 CRE-.IFT80f/f mice. After 5 and 12 days of orthodontic force loading, the orthodontic tooth movement distance and bone parameters were evaluated using microCT. Osteoclast formation was assessed using TRAP-stained paraffin sections. The expression of sclerostin and RANKL was examined using immunofluorescence stain. We found that the deletion of IFT80 in osteocytes did not significantly impact either orthodontic or physiologic bone remodeling, as demonstrated by similar OTM distances, osteoclast numbers, bone volume fractions (bone volume/total volume), bone mineral densities, and the expressions of sclerostin and RANKL. Our findings suggest that there are other possible mechanosensory systems in osteocytes and anatomic limitations to cilia deflection in osteocytes in vivo.

Macrophage regulator of G-protein signaling 12 contributes to inflammatory pain hypersensitivity.

BACKGROUND: Pain is a predominant symptom in rheumatoid arthritis (RA) patients that results from joint inflammation and is augmented by central sensitization. Regulator of G-protein signaling 12 (RGS12) is the largest protein in the RGS protein family and plays a key role in the development of inflammation. This study investigated the regulation of RGS12 in inflammatory pain and explored the underlying mechanisms and potential RA pain targets. METHODS: Macrophage-specific RGS12-deficient (LysM-Cre+;RGS12fl/fl) mice were generated by mating RGS12fl/fl mice with LysM-Cre+ transgenic mice. Collagen antibody-induced arthritis (CAIA) models were induced in LysM-Cre+;RGS12fl/fl mice by the administration of a cocktail of five monoclonal antibodies and LPS. Mouse nociception was examined using the von Frey and heat plate tests. Primary macrophages and RAW264.7 cells were used to analyze the regulatory function and mechanism of RGS12 in vitro. The expression and function of RGS12 and COX2 (cyclooxygenase 2) were determined by real-time PCR, ELISA, and luciferase assays. RESULTS: Ablation of RGS12 in macrophages decreased pain-related phenotypes, such as paw swelling, the clinical score, and the inflammatory score, in the CAIA model. LysM-Cre+;RGS12fl/fl mice displayed increased resistance to thermal and mechanical stimulation from day 3 to day 9 during CAIA, indicating the inhibition of inflammatory pain. Overexpression of COX2 and PGE2 in macrophages enhanced RGS12 expression, and PGE2 regulated RGS12 expression through the G-protein-coupled receptors EP2 and EP4. Furthermore, RGS12 or the RGS12 PTB domain strengthened the transcriptional regulation of COX2 by NF-κB, whereas inhibiting NF-κB suppressed RGS12-mediated regulation of COX2 in macrophages. CONCLUSIONS: Our results demonstrate that the deletion of RGS12 in macrophages attenuates inflammatory pain, which is likely due to impaired regulation of the COX2/PGE2 signaling pathway.

RGS12 is required for the maintenance of mitochondrial function during skeletal development.

Mitochondrial morphology and function are crucial for tissue homeostasis, such as for skeletal development, but the cellular and molecular mechanisms remain unclear. Here, we provide evidence that regulator of G-protein signaling 12 (RGS12) is present in the mitochondria of primary chondrocytes and cartilage tissues. Deletion of RGS12 in type II collagen-positive cells led to a significant decrease in mitochondrial number, membrane potential, and oxidative phosphorylation function. Mechanistically, RGS12 promoted the function of ATP5A as an enhancer of tyrosine phosphorylation. Mice with RGS12 deficiency in the chondrocyte lineage showed serious body retardation, decreased bone mass, and chondrocyte apoptosis due to the defective activity of ATP synthase. To our knowledge, this is the first report that RGS12 is required for maintaining the function of mitochondria, which may allow it to orchestrate responses to cellular homeostasis.

RGS12 Is a Novel Critical NF-κB Activator in Inflammatory Arthritis.

Rheumatoid arthritis (RA) is the most common inflammatory disease, which currently lacks effective treatment. Here, we discovered that the Regulator of G Protein Signaling 12 (RGS12) plays a key role in regulating inflammation. Transcriptional and protein analysis revealed that RGS12 was upregulated in human and mouse RA macrophages. Deletion of RGS12 in myeloid lineage or globally inhibits the development of collagen-induced arthritis including joint swelling and bone destruction. Mechanistically, RGS12 associates with NF-κB(p65) to activate its phosphorylation and nuclear translocation through PTB domain, and NF-κB(p65) regulates RGS12 expression in a transcriptional manner. The nuclear translocation ability of NF-κB(p65) and RGS12 can both be enhanced by cyclooxygenase-2 (COX2). Furthermore, ablation of RGS12 via RNA interference significantly blocks the inflammatory process in vivo and in vitro. These results demonstrate that RGS12 plays a critical role in the pathogenesis of inflammatory arthritis.

The circadian protein CLOCK regulates cell metabolism via the mitochondrial carrier SLC25A10.

Physiological function and metabolic regulation are the most important outputs of circadian clock controls in mammals. Mitochondrial respiration and ROS production show rhythmic activity. Mitochondrial carriers, which are responsible for mitochondrial substance transfer, are vital for mitochondrial metabolism. Clock (Circadian Locomotor Output Cycles Kaput) is the first core circadian gene identified in mammalian animals. However, whether CLOCK protein can regulate mitochondrial functions via mitochondrial carriers is unclear. Here, we showed that CLOCK can bind to the mitochondrial carrier SLC25A10. For further analysis, we established a Slc25a10-/--Hepa1-6 cell line using CRISPR/Cas9 gene-editing technology. Slc25a10-/--Hepa1-6 cells showed disordered glucose homeostasis, increased oxidative stress levels, and damaged electron transport chains. Next, using an immunoprecipitation assay, we found that amino acids 43-84 and 169-210 in SLC25A10 are key sites that respond to CLOCK binding. Finally, forced expression of wild-type SLC25A10 in Slc25a10-/--Hepa1-6 cells could compensate for the loss of SLC25A10; the decreased glucose metabolism, severe oxidative stress and damaged electron transport chain were recovered. In addition, a mutant Slc25a10 with changes in two key sites did not show a rescue effect. In conclusion, we identified a new protein-protein interaction mechanism in which CLOCK can directly regulate cell metabolism via the mitochondrial membrane transporter SLC25A10. Our study might provide some new insights into the relationship between circadian clock and mitochondrial metabolism.

The Circadian Gene Clock Regulates Bone Formation Via PDIA3.

The expression patterns of clock-controlled genes (ccgs) are regulated by circadian rhythm, which is a major regulatory and physiological mechanism tied to the solar day. Disruptions in circadian rhythm contribute to the development of cardiovascular diseases, cancer, metabolic syndromes, and aging. It has been reported that bone remodeling is also regulated by circadian rhythm. However, the molecular mechanism by which the circadian gene Clock regulates bone remodeling has yet to be elucidated. Here, we show that Clock mutant mice exhibit a significant reduction in bone density as well as increased apoptosis. Protein disulfide isomerase family A member 3 (PDIA3) is a 1,25-dihydroxy-vitamin D3 [1α,25(OH)2D3] receptor that can regulate bone formation and apoptosis. Using luciferase and ChIP assays, we confirmed that Pdia3 is a ccg. Clock activates Pdia3 transcription by binding the E-box promoter, and transcription is decreased in ClockΔ19 mutant mice. Forced expression of Pdia3 or of Clock completely rescues the osteogenic disorders found in the mutant background and inhibits apoptosis in vivo and in vitro. Furthermore, ablation of PDIA3 via RNA interference completely blocks the compensatory effect of forced expression of Clock in osteoblasts. Our results demonstrate that the core circadian gene Clock regulates bone formation via transcriptional control of 1,2,5(OH)2D3 receptor PDIA3. © 2016 American Society for Bone and Mineral Research.

Clock mediates liver senescence by controlling ER stress.

Accumulated evidence indicates that circadian genes regulate cell damage and senescence in most mammals. Endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) regulate longevity in many organisms. However, the specific mechanisms of the relationship between the circadian clock and the two stress processes in organisms are poorly understood. Here, we show that Clock-mediated Pdia3 expression is required to sustain reactive oxidative reagents and ER stress. First, ER stress and ROS are strongly activated in the liver tissue of Clock∆19 mutant mice, which exhibit a significant aging phenotype. Next, transcription of Pdia3 is mediated by the circadian gene Clock, but this process is affected by the Clock∆19 mutant due to the low affinity of the E-box motif in the promoter. Finally, ablation of Pdia3 with siRNA causes ER stress with sustained phosphorylation of PERK and eIF1α, resulting in exaggerated up-regulation of UPR target genes and increased apoptosis as well as ROS. Moreover, the combined effects result in an imbalance of cell homeostasis and ultimately lead to cell damage and senescence. Taken together, this study identified the circadian gene Clock as a regulator of ER stress and senescence, which will provide a reference for the clinical prevention of aging.

Altered Clock and Lipid Metabolism-Related Genes in Atherosclerotic Mice Kept with Abnormal Lighting Condition.

Background. The risk of atherosclerosis is elevated in abnormal lipid metabolism and circadian rhythm disorder. We investigated whether abnormal lighting condition would have influenced the circadian expression of clock genes and clock-controlled lipid metabolism-related genes in ApoE-KO mice. Methods. A mouse model of atherosclerosis with circadian clock genes expression disorder was established using ApoE-KO mice (ApoE-KO LD/DL mice) by altering exposure to light. C57 BL/6J mice (C57 mice) and ApoE-KO mice (ApoE-KO mice) exposed to normal day and night and normal diet served as control mice. According to zeitgeber time samples were acquired, to test atheromatous plaque formation, serum lipids levels and rhythmicity, clock genes, and lipid metabolism-related genes along with Sirtuin 1 (Sirt1) levels and rhythmicity. Results. Atherosclerosis plaques were formed in the aortic arch of ApoE-KO LD/DL mice. The serum lipids levels and oscillations in ApoE-KO LD/DL mice were altered, along with the levels and diurnal oscillations of circadian genes, lipid metabolism-associated genes, and Sirt1 compared with the control mice. Conclusions. Abnormal exposure to light aggravated plaque formation and exacerbated disorders of serum lipids and clock genes, lipid metabolism genes and Sirt1 levels, and circadian oscillation.