Nuclear Lipid Microdomain as Place of Interaction between Sphingomyelin and DNA during Liver Regeneration

Abstract

Nuclear sphingomyelin is a key molecule for cell proliferation. This molecule is organized with cholesterol and proteins to form specific lipid microdomains bound to the inner nuclear membrane where RNA is synthesized. Here, we have reported the ability of the sphingomyelin present in the nuclear microdomain to bind DNA and regulate its synthesis, and to highlight its role in cell proliferation induced by partial hepatectomy. During G1/S transition of the cell cycle, sphingomyelin and DNA content is very high and it is strongly reduced after exogenous sphingomyelinase treatment. During the S-phase of the cell cycle, the stimulation of sphingomyelinase and inhibition of sphingomyelin–synthase are accompanied by the DNA synthesis start. To assess the specificity of the results, experiments were repeated with trifluoperazine, a drug known to affect the synthesis of lipids and DNA and to stimulate sphingomyelinase activity. The activity of sphingomyelinase is stimulated in the first hour after hepatectomy and sphingomyelin–DNA synthesis is strongly attenuated. It may be hypothesized that the nuclear microdomain represents a specific area of the inner nuclear membrane that acts as an active site of chromatin anchorage thanks to the stabilizing action of sphingomyelin. Thus, sphingomyelin metabolism in nuclear lipid microdomains is suggested to regulate cell proliferation.

Role of sphingomyelinases in neurological disorders

“…Nuclear sphingomyelin is present in the perichromatin region and the nucleolus, in association with dense fibrils containing transcriptionally active ribosomal genes [70]. It is postulated that sphingomyelin has a stabilizing action on microdomains in the inner nuclear membrane that act as sites of chromatin anchorage for DNA and RNA synthesis [71,72]. A downstream product of sphingomyelin activity S1P is present in the nucleus, and has an important function in epigenetic regulation of gene expression.…”

Localization of nuclear actin in nuclear lipid microdomains of liver and hepatoma cells: Possible involvement of sphingomyelin metabolism

“…In this study, we attempted to delineate the domains responsible for nuclear β-actin localization. Therefore our work has identified for the first time the association of nuclear β-actin with specific lipid microdomains present in inner NM that acts as platform for Chr anchoring, DNA duplication and transcription (8,9,10). Therefore it is possible that the β-actin, binding to NLM, plays a role of key molecule involved in the active chromatin function.…”

“…In Chr, SMase activity increases and SM-synthase activity decreases; the opposite happens in NLM. This apparent contradiction could be explained with the different roles of SM in Chr (14,19) and in NLM (8,9,10).…”

Lipids contribute to epigenetic control via chromatin structure and functions

“…On this basis, it was proposed that nuclear lipid microdomains might serve as a platform for transcription. These were suggested to be the anchoring point of the active chromatin in liver cells [50]. In a recent study of normal and cancer cells from liver, the authors found differences not only in the lipid composition of the nuclear lipid rafts and lipid microdomains, but also in the proteins involved in carcinogenesis associated with these structures, such as STAT3, Raf1, and PKCζ [51].…”