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Cell Cycle. 2016; 15(22): 3020–3021.
Published online 2016 August 2. doi:  10.1080/15384101.2016.1216924
PMCID: PMC5134694

Metabolic demand of the hepatic cell cycle

Lipid metabolism has been considered an important aspect of hepatocyte proliferation. After partial hepatectomy (PH) of the liver, a massive program of tissue regeneration and proliferation is induced. The role of lipids, both cholesterol and triglycerides (TG), in the regenerating liver following PH is believed to be critical.1,2 Yet, the precise role of lipids in liver regeneration have yielded somewhat diverging results. Specifically, diet-induced fat accumulation in liver using western or high fat diet resulted in impaired liver regeneration,3 while suppression of hepatocyte-derived fat accumulation resulted in impaired proliferation of the liver following PH.4 Interestingly, these results potentially suggest that a balance of fats may be required, and levels of specific lipids may need to be tightly controlled in the regenerating liver following PH.

To further investigate this, Bartoli et al. utilized a mouse model lacking the Tm7sf2 gene that encodes 3 β-hydroxysterol-Δ14-reductase (C14-SR), a critical enzyme involved in cholesterol biosynthesis. Strikingly, these mice do not display any differences in liver or plasma cholesterol levels. Yet, wild-type (WT) mice exhibit a biphasic accumulation in liver TG which first peak at 8 hours and again at 36 hours post PH, possibly suggesting a metabolic demand in the liver at 2 different time points during the regenerative process.5 This biphasic profile of lipid levels is in contrast to the Tm7sf2 knockout (KO) mice which display elevated but delayed accumulation of TG levels at 38–72 hours post PH.5 Based on BrdU incorporation as an indication of cell proliferation, KO mice exhibit overall significant loss of hepatocyte proliferative capacity following PH. These results strongly related with data showing that markers of G1/S and G2/M cell cycle progression were decreased in KO mice. For example, gene and protein expression of Cyclin D1, CDK4, and Cyclin A were constitutively repressed during all time points, in addition to loss of phospho-H3 in KO mice post PH.5 These results were correlated with an increase in the unfolded protein response (UPR) triggered by ER stress in KO mice post PH. The authors observed an accumulation in p53 levels which induced levels of p21, a regulator of cell cycle arrest, in KO mice post PH (Fig. 1).5

Figure 1.
Role of lipid metabolism in cell cycle progression in the liver. Triglyceride levels in the proliferating liver after partial hepatectomy are involved in the G1/S and G2/M phases of cell cycle regulation. In contrast, when lipid metabolism is disrupted ...

Overall this study highlights the precisely timed cellular requirement for TG levels in the regenerating liver post PH. This heightened metabolic demand is correlated with the cell cycle in WT liver and accumulation of TG levels in Tm7sf2 KO mice at the improper time results in stress-induced arrest of the cell cycle and corresponding loss of proliferative capacity. The authors provide key evidence for the specific need of TG in the liver during regeneration, yet the question regarding specific lipid types and their precise timing during certain phases of the cell cycle is quite intriguing. In addition, we can imagine that multiple aspects of lipid metabolism could be altered in KO mice post PH. Is this TG accumulation in KO mice a result of altered fatty acid biosynthesis or even breakdown by β-oxidation? As an example, Sterol regulatory element-binding protein 1a (SREBP1a) was found to be involved in CDK4-dependent cell cycle arrest,6 could this lipid biosynthetic transcriptional program be playing a similar role in KO mice post PH? Moreover, are the increased levels of TG simply a result of improperly utilized lipids due to misalignment with the cell cycle? What is the specific metabolic cue that is causing this delay and accumulation in TG levels in KO mice post PH? Lastly, are the elevated TG levels in KO mice post PH due to changes in enzymes involved in storage of free fatty acids into TG? These ideas highlight a number of very important questions that emerge from this study that could provide a wealth of knowledge about the critical role of lipid metabolism and cellular energetic demand in the regenerating liver post PH.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.


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