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Sołtysik et al. show that the inner nuclear membrane of nonhepatocytes harbors triglyceride synthesis enzymes and generates nuclear lipid droplets (LDs). Seipin knockdown increases nuclear LDs through upregulating lipin-1β transcription and increasing phosphatidic acid levels in the nucleus., Nuclear lipid droplets (LDs) in hepatocytes are derived from precursors of very-low-density lipoprotein in the ER lumen, but it is not known how cells lacking the lipoprotein secretory function form nuclear LDs. Here, we show that the inner nuclear membrane (INM) of U2OS cells harbors triglyceride synthesis enzymes, including ACSL3, AGPAT2, GPAT3/GPAT4, and DGAT1/DGAT2, and generates nuclear LDs in situ. mTOR inhibition increases nuclear LDs by inducing the nuclear translocation of lipin-1 phosphatidic acid (PA) phosphatase. Seipin, a protein essential for normal cytoplasmic LD formation in the ER, is absent in the INM. Knockdown of seipin increases nuclear LDs and PA in the nucleus, whereas seipin overexpression decreases these. Seipin knockdown also up-regulates lipin-1β expression, and lipin-1 knockdown decreases the effect of seipin knockdown on nuclear LDs without affecting PA redistribution. These results indicate that seipin is not directly involved in nuclear LD formation but instead restrains it by affecting lipin-1 expression and intracellular PA distribution.

The origin and physiological significance of lipid droplets (LDs) in the nucleus is not clear. Here we show that nuclear LDs in hepatocytes are derived from apolipoprotein B (ApoB)-free lumenal LDs, a precursor to very low-density lipoproprotein (VLDL) generated in the ER lumen by microsomal triglyceride transfer protein. ApoB-free lumenal LDs accumulate under ER stress, grow within the lumen of the type I nucleoplasmic reticulum, and turn into nucleoplasmic LDs by disintegration of the surrounding inner nuclear membrane. Oleic acid with or without tunicamycin significantly increases the formation of nucleoplasmic LDs, to which CTP:phosphocholine cytidylyltransferase α (CCTα) is recruited, resulting in activation of phosphatidylcholine (PC) synthesis. Perilipin-3 competes with CCTα in binding to nucleoplasmic LDs, and thus, knockdown and overexpression of perilipin-3 increases and decreases PC synthesis, respectively. The results indicate that nucleoplasmic LDs in hepatocytes constitute a feedback mechanism to regulate PC synthesis in accordance with ER stress.

Lipid droplets (LDs) are often found adjacent to the endoplasmic reticulum (ER). The ER-LD association may appear morphologically similar to the prototypical membrane contact sites found between the ER and other organelles, but the functional relationship between the ER and LDs is unique in that highly hydrophobic lipid esters are transported between them. This transportation is thought to occur through some form of membrane continuity, but its details are yet to be defined. Lipin, seipin, and FIT proteins, which are located at the ER-LD interface, may be involved in the lipid ester transport and probably play important roles for functional connectivity of the two organelles. More recently, LDs in the nucleus were found to be closely adhered to the inner nuclear membrane, representing a specialized form of the ER-LD association. In this article, we will give an overview of the ER-LD association, which is still filled with many unanswered questions.

Although the nuclear action of estrogen receptors (ER) is a well-known fact, evidence supporting membrane estrogen receptors is steadily accumulating. New ER variants of unrecognized function have been discovered. ERα is a product of the ESR1 gene. It serves not only as a template for the full-length 66kDa protein, but also for smaller isoforms which exist as independent receptors. The recently discovered ERα36 (36kDa), consisting of 310 amino acids of total 595 ERα66 protein residues, is an example of that group. The transcription initiation site is identified in the first intron of the ESR1 gene. C-Terminal 27 amino acids are encoded by previously unknown exon 9. The presence of this unique C-terminal sequence creates an opportunity for the production of selective antibodies. ERα36 has been shown to have a high affinity to the cell membrane and as much as 90% of the protein can be bound with it. Post-translational palmitoylation is suspected to play a crucial role in ERα36 anchoring to the cell membrane. In silico analysis suggests the existence of a potential transmembrane domain in ERα36. ERα36 was found in most cells of animals at various ages, but its exact physiological function remains to be fully elucidated. It seems that cells traditionally considered as being deprived of ER are able to respond to hormonal stimulation via the ERα36 receptor. Moreover, ERα36 displays unique pharmacological properties and its action may be behind antiestrogen resistance. The use of ERα36 in cancer diagnosis gives rise to great expectations.