Cyclin D1 represses peroxisome proliferator-activated receptor alpha and inhibits fatty acid oxidation

Kamarajugadda, Sushama; Becker, Jennifer R.; Hanse, Eric A.; Mashek, Douglas G.; Mashek, Mara T.; Hendrickson, Anna M.; Mullany, Lisa K.; Albrecht, Jeffrey H.

doi:10.18632/oncotarget.10274

Cited by 26 publications

(45 citation statements)

References 53 publications

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“…. As previously shown, ADV‐mediated transduction of cells with cyclin D1 induced cell cycle progression in the absence of growth factor (as measured by DNA synthesis), whereas siRNA‐mediated knockdown of this protein diminished mitogen‐stimulated proliferation (Fig. A,B).…”

Section: Resultssupporting

confidence: 74%

Evidence for a Novel Regulatory Interaction Involving Cyclin D1, Lipid Droplets, Lipolysis, and Cell Cycle Progression in Hepatocytes

Ploeger

Kamarajugadda

et al. 2019

Hepatol Commun

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During normal proliferation, hepatocytes accumulate triglycerides (TGs) in lipid droplets (LDs), but the underlying mechanisms and functional significance of this steatosis are unknown. In the current study, we examined the coordinated regulation of cell cycle progression and LD accumulation. As previously shown, hepatocytes develop increased LD content after mitogen stimulation. Cyclin D1, in addition to regulating proliferation, was both necessary and sufficient to promote LD accumulation in response to mitogens. Interestingly, cyclin D1 promotes LD accumulation by inhibiting the breakdown of TGs by lipolysis through a mechanism involving decreased lipophagy, the autophagic degradation of LDs. To examine whether inhibition of lipolysis is important for cell cycle progression, we overexpressed adipose TG lipase (ATGL), a key enzyme involved in TG breakdown. As expected, ATGL reduced LD content but also markedly inhibited hepatocyte proliferation, suggesting that lipolysis regulates a previously uncharacterized cell cycle checkpoint. Consistent with this, in mitogen‐stimulated cells with small interfering RNA‐mediated depletion of cyclin D1 (which inhibits proliferation and stimulates lipolysis), concurrent ATGL knockdown restored progression into S phase. Following partial hepatectomy, a model of robust hepatocyte proliferation in vivo, ATGL overexpression led to decreased LD content, cell cycle inhibition, and marked liver injury, further indicating that down‐regulation of lipolysis is important for normal hepatocyte proliferation. Conclusion: We suggest a new relationship between steatosis and proliferation in hepatocytes: cyclin D1 inhibits lipolysis, resulting in LD accumulation, and suppression of lipolysis is necessary for cell cycle progression.

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Section: Resultssupporting

confidence: 74%

Evidence for a Novel Regulatory Interaction Involving Cyclin D1, Lipid Droplets, Lipolysis, and Cell Cycle Progression in Hepatocytes

Ploeger

Kamarajugadda

et al. 2019

Hepatol Commun

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“…CyclinD1, expressed in proliferating cells and a typical protooncogene, was found to inhibit PPAR α expression, thereby reducing β -oxidation, both in normal hepatocytes and in HCC cells lines. This link was confirmed also in liver after partial hepatectomy, where induction of CyclinD1 timed with a reduction of PPAR α and its target genes [101]. …”

Section: Ppars and Mitochondrial Dysfunction From Nafld To Hccmentioning

confidence: 82%

PPARs and Mitochondrial Metabolism: From NAFLD to HCC

2016

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Metabolic related diseases, such as type 2 diabetes, metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD), are widespread threats which bring about a significant burden of deaths worldwide, mainly due to cardiovascular events and cancer. The pathogenesis of these diseases is extremely complex, multifactorial, and only partially understood. As the main metabolic organ, the liver is central to maintain whole body energetic homeostasis. At the cellular level, mitochondria are the metabolic hub connecting and integrating all the main biochemical, hormonal, and inflammatory signaling pathways to fulfill the energetic and biosynthetic demand of the cell. In the liver, mitochondria metabolism needs to cope with the energetic regulation of the whole body. The nuclear receptors PPARs orchestrate lipid and glucose metabolism and are involved in a variety of diseases, from metabolic disorders to cancer. In this review, focus is placed on the roles of PPARs in the regulation of liver mitochondrial metabolism in physiology and pathology, from NAFLD to HCC.

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“…Cyclin D1 inhibits the transcriptional activity of PPARγ. It also enhances the recruitment of HDAC and histone methyltransferase (such as SuV39H) to the PPAR-response element [76] and inhibits the transcriptional activity of PPARα through an unknown mechanism, thereby acting on fatty acid metabolism and energy homeostasis [20]. The oncogenic function of cyclin D1-mediated PPARs activation remains to be established.…”

Section: Nuclear Cyclin D1 Controls Transcriptionmentioning

confidence: 99%

The double dealing of cyclin D1

2019

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Abbreviations: aa, amino acid ; AR, androgen receptor; ATM, ataxia telangectasia mutant;ATR, ATM and Rad3-related; CDK, cyclin-dependent kinase; ChREBP, carbohydrate response element binding protein; CIP, CDK-interacting protein; CHK1/2, checkpoint kinase 1/2; CKI, CDK inhibitor; DDR, DNA damage response; DMP1, cyclin D-binding myb-like protein; DSB, double-strand DNA break; DNA-PK, DNA-dependent protein kinase; ER, estrogen receptor; FASN, fatty acid synthase; GSK3β, glycogen synthase-3β; HAT, histone acetyltransferase; HDAC, histone deacetylase; HK2, hexokinase 2; HNF4α, and hepatocyte nuclear factor 4α; HR, homologous recombination; IR, ionizing radiation; KIP, kinase inhibitory protein; MCL, mantle cell lymphoma; NHEJ, non-homologous end-joining; PCAF, p300/CREB binding-associated protein; PGC1α, PPARγ co-activator 1α; PEST, proline-glutamic acid-serine-threonine, PK, pyruvate kinase; PPAR, peroxisome proliferator-activated receptor; RB1, retinoblastoma protein; ROS, reactive oxygen species; SRC, steroid receptor coactivator; STAT, signal transducer and activator of transcription; TGFβ, transforming growth factor β; UPS, ubiquitinproteasome system; USP22, ubiquitin-specific peptidase 22; XPO1 (or CRM1) exportin 1. AbstractThe cell cycle is tightly regulated by cyclins and their catalytic moieties, the cyclindependent kinases (CDKs). Cyclin D1, in association with CDK4/6, acts as a mitogenic sensor and integrates extracellular mitogenic signals and cell cycle progression. When deregulated (overexpressed, accumulated, inappropriately located), cyclin D1 becomes an oncogene and is recognized as a driver of solid tumors and hemopathies. Recent studies on the oncogenic roles of cyclin D1 reported non-canonical functions dependent on the partners of cyclin D1 and its location within tumor cells or tissues. Support for these new functions was provided by various mouse models of oncogenesis. Finally, proteomic and transcriptomic data identified complex cyclin D1 networks. This review focuses on these aspects of cyclin D1 pathophysiology, which may be crucial for targeted therapy.

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Cyclin D1 represses peroxisome proliferator-activated receptor alpha and inhibits fatty acid oxidation

Cited by 26 publications

References 53 publications

Evidence for a Novel Regulatory Interaction Involving Cyclin D1, Lipid Droplets, Lipolysis, and Cell Cycle Progression in Hepatocytes

Evidence for a Novel Regulatory Interaction Involving Cyclin D1, Lipid Droplets, Lipolysis, and Cell Cycle Progression in Hepatocytes

PPARs and Mitochondrial Metabolism: From NAFLD to HCC

The double dealing of cyclin D1

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