Distinct features of two lipid droplets types in cell nuclei from patients with liver diseases

Abstract

Lipid droplets (LDs) have been observed in the nuclei of hepatocytes; however, their significance in liver disease remains unresolved. Our purpose was to explore the pathophysiological features of intranuclear LDs in liver diseases. We included 80 patients who underwent liver biopsies; the specimens were dissected and fixed for electron microscopy analysis. Depending on the presence of adjacent cytoplasmic invagination of the nuclear membrane, LDs in the nuclei were classified into two types: nucleoplasmic LDs (nLDs) and cytoplasmic LD invagination with nucleoplasmic reticulum (cLDs in NR). nLDs were found in 69% liver samples and cLDs in NR were found in 32%; no correlation was observed between the frequencies of the two LD types. nLDs were frequently found in hepatocytes of patients with nonalcoholic steatohepatitis, whereas cLDs in NR were absent from the livers of such patients. Further, cLDs in NR were often found in hepatocytes of patients with lower plasma cholesterol level. This indicates that nLDs do not directly reflect cytoplasmic lipid accumulation and that formation of cLDs in NR is inversely correlated to the secretion of very low-density lipoproteins. Positive correlations were found between the frequencies of nLDs and endoplasmic reticulum (ER) luminal expansion, suggesting that nLDs are formed in the nucleus upon ER stress. This study unveiled the presence of two distinct nuclear LDs in various liver diseases.

Nuclear lipid droplets in Caco2 cells originate from nascent precursors and in situ at the nuclear envelope

“…A similar diversion of TAG to nLDs occurred in a mouse liver knockout of the lamin-associated protein 1, which caused steatosis and accumulation of large nLDs due to inhibition of VLDL secretion ( 3 , 48 ). Hepatic nonalcoholic steatosis is also reported to increase the abundance of nLDs ( 49 ). Similarly, our studies describe how nLD assemble in Caco2 cells; however, whether this applies to normal cells, and the pathological mechanisms that promote accumulation of these novel lipid stress-induced nuclear subdomains, is still unknown.…”

Review article: Hepatic steatosis and its associations with acute and chronic liver diseases

“…181 However, mechanisms of nuclear LD formation 178 and regulation of lipin-1 localisation by mTORC appear to be cell-type specific, 181 complicating interpretation of results. Nevertheless, nuclear LDs are a common finding by electron microscopy in CLD according to Imai et al, 182 with the presence of LDs in association with type 1 NR correlating with markers of ER luminal size and ER stress, while type 2 NR-derived LDs were found in patients with lower serum total cholesterol and LDL levels. 182…”

“…Nevertheless, nuclear LDs are a common finding by electron microscopy in CLD according to Imai et al, 182 with the presence of LDs in association with type 1 NR correlating with markers of ER luminal size and ER stress, while type 2 NR-derived LDs were found in patients with lower serum total cholesterol and LDL levels. 182…”

Zooming into lipid droplet biology through the lens of electron microscopy

“…While the vast majority of LDs are cytoplasmic, emerging evidence suggests intranuclear LDs are prominent features of many cell types, including yeast [19], cultured mammalian cells [23], Caenorhabditis elegans tissues [93], and human liver samples (Fig. 1J) [21,94]. Importantly, the initial unambiguous characterization of nuclear LDs as true nucleoplasmic organelles (vs. cytoplasmic LDs simply invaginating into the nucleus) necessitated the use of high-resolution 3D EM, such as serial section TEM (Fig.…”