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

Abstract

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.

Adipose triglyceride lipase activity regulates cancer cell proliferation via AMP-kinase and mTOR signaling

“…In MEFs, overexpression of ATGL decreased, while ATGL deficiency increased cellular TG levels and cell proliferation rates. These results are consistent with data suggesting that ATGL-mediated TG breakdown regulates cell cycle checkpoints and proliferation of primary hepatocytes [ 42 ]. Reduced ATGL expression and subsequently altered TG hydrolysis was shown to impair mitochondrial FAO, leading to a shift in substrate utilization in hepatocytes [ [43] , [44] , [45] ].…”

Pharmacologic Inhibition of Epidermal Growth Factor Receptor Suppresses Nonalcoholic Fatty Liver Disease in a Murine Fast‐Food Diet Model

“…This proliferation‐associated lipid accumulation may have a compounding effect on an already steatotic liver during NAFLD and may contribute to progression of the disease. Recent studies indicate a role of the key cell cycle protein cyclin D1, which governs entry into the cell cycle, in regeneration‐associated steatosis and lipid metabolism, in general . Here, we show that FFD feeding for 5 months induces robust hepatocyte proliferation as evidenced by an increase in proliferating cell nuclear antigen (PCNA)–positive hepatocytes, which was dramatically reduced by EGFR inhibition (Fig.…”

Myrtenal Modulates the Immunoexpression of Cell Proliferative, Angiogenic and Invasive Markers in DMBA-Induced Hamster Oral Carcinogenesis

“…Cyclin D1 is an important gene that has been reported to play a pivotal role in the regulation of cell cycle phases and cell signals. 35 The cyclin D1 overexpression has been shown in the G1 phase of the cell cycle and abnormal or aberrant cell proliferation. 36,37 As several cancerous tissues have shown an aberrant expression of cyclin D1, inhibition of cyclin D1 expression has recently been considered as a major target for therapeutic implications.…”