Impaired cell proliferation in regenerating liver of 3 β-hydroxysterol Δ14-reductase (TM7SF2) knock-out mice

Abstract

The liver is the most important organ in cholesterol metabolism, which is instrumental in regulating cell proliferation and differentiation. The gene Tm7sf2 codifies for 3 b-hydroxysterol-D 14 -reductase (C14-SR), an endoplasmic reticulum resident protein catalyzing the reduction of C14-unsaturated sterols during cholesterol biosynthesis from lanosterol. In this study we analyzed the role of C14-SR in vivo during cell proliferation by evaluating liver regeneration in Tm7sf2 knockout (KO) and wild-type (WT) mice. Tm7sf2 KO mice showed no alteration in cholesterol content. However, accumulation and delayed catabolism of hepatic triglycerides was observed, resulting in persistent steatosis at all times post hepatectomy. Moreover, delayed cell cycle progression to the G1/S phase was observed in Tm7sf2 KO mice, resulting in reduced cell division at the time points examined. This was associated to abnormal ER stress response, leading to alteration in p53 content and, consequently, induction of p21 expression in Tm7sf2 KO mice. In conclusion, our results indicate that Tm7sf2 deficiency during liver regeneration alters lipid metabolism and generates a stress condition, which, in turn, transiently unbalances hepatocytes cell cycle progression.

HOPS/TMUB1 retains p53 in the cytoplasm and sustains p53‐dependent mitochondrial apoptosis

“…All the images were exported in TIFF, contrast and brightness were adjusted in Corel PaintShop Pro ×9 and final figures were generated with Adobe Illustrator CS6 [57]. All the images were exported in TIFF, contrast and brightness were adjusted in Corel PaintShop Pro ×9 and final figures were generated with Adobe Illustrator CS6 [57].…”

Metabolic demand of the hepatic cell cycle

“…1). 5 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.…”

“…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.…”

“…Yet, wildtype (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.…”

“…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.…”