Perilipin 1 Expression Differentiates Liposarcoma from Other Types of Soft Tissue Sarcoma.

Lipid droplets, a morphologic feature of adipocytic tumors, are strongly regulated by associated proteins of the perilipin/PAT (perilipin, adipophilin, and tail-interacting protein of 47 kD) family. So far, the use of perilipins as markers for differential diagnosis of soft tissue tumors has only been studied in a few cases. The aim of this study was to investigate the expression of perilipins in 478 human soft tissue tumors and 60 respective normal tissues. Perilipin 1 was immunohistochemically positive in all studied cases of well-differentiated liposarcomas, >90% of myxoid round cell liposarcomas, and >70% of pleomorphic liposarcomas, whereas only the differentiated components of dedifferentiated liposarcomas were immunohistochemically positive for perilipin 1. All other types of soft tissue sarcomas were negative for perilipin 1. Perilipin 2 was more prominent in dedifferentiated and pleomorphic liposarcomas and nearly all other high-grade sarcomas. In well-differentiated liposarcomas, lipomas, or normal adipose tissue, perilipin 2 was virtually absent. In addition, long-term stimulation of adipogenesis in the liposarcoma cell line LiSa-2 restored perilipin 1 expression, as exhibited in the source tumor. Furthermore, knockdown of perilipin 2 or perilipin 3 in LiSa-2 cells influenced lipid droplet number and size as well as cell vitality. In summary, perilipin 1 is a promising marker for the differential diagnosis of liposarcomas from other soft tissue sarcomas, whereas perilipin 2 correlates negatively with tumor grade and may be therapeutically useful.

Widespread expression of perilipin 5 in normal human tissues and in diseases is restricted to distinct lipid droplet subpopulations.

Diseases associated with the accumulation of lipid droplets are increasing in western countries. Lipid droplet biogenesis, structure and degradation are regulated by proteins of the perilipin family. Perilipin 5 has been shown to regulate basal lipolysis in oxidative tissues. We examine perilipin 5 in normal human tissues and in diseases using protein biochemical and microscopic techniques. Perilipin 5 was constitutively located at small lipid droplets in skeletal myocytes, cardiomyocytes and brown adipocytes. In addition, perilipin 5 was detected in the epithelia of the gastrointestinal and urogenital tract, especially in hepatocytes, the mitochondria-rich parietal cells of the stomach, tubular kidney cells and ductal cells of the salivary gland and pancreas. Granular cytoplasmic expression, without a lipid droplet-bound localization was detected elsewhere. In cardiomyopathies, in skeletal muscle diseases and during hepatocyte steatogenesis, perilipin 5 was upregulated and localized to larger and more numerous lipid droplets. In steatotic human hepatocytes, perilipin 5 was moderately increased and colocalized with perilipins 1 and 2 but not with perilipin 3 at lipid droplets. In liver diseases implicated in alterations of mitochondria, such as mitochondriopathies, alcoholic liver disease, Wilson's disease and acute liver injury, perilipin 5 was frequently localized to small lipid droplets and less in the cytoplasm. In tumorigenesis, perilipin 5 was especially upregulated in lipo-, leio- and rhabdomyosarcoma and hepatocellular and renal cell carcinoma. In summary, our study provides evidence that perilipin 5 is not restricted to certain cell types but localizes to distinct lipid droplet subpopulations reflecting a possible function in oxidative energy supply in normal tissues and in diseases.

Perilipin discerns chronic from acute hepatocellular steatosis.

BACKGROUND & AIMS: Hepatocellular steatosis is the most frequent liver disease in the western world and may develop further to steatohepatitis, liver cirrhosis and hepatocellular carcinoma. We have previously shown that lipid droplet (LD)-associated proteins of the perilipin/PAT-family are differentially expressed in hepatocyte steatosis and that perilipin is expressed de novo. The aim of this study was to determine the conditions for the temporal regulation of de novo synthesis of perilipin in vitro and in vivo. METHODS: Immunohistochemical PAT-analysis was performed with over 120 liver biopsies of different etiology and duration of steatosis. Steatosis was induced in cultured hepatocytic cells with combinations of lipids, steatogenic substances and DMSO for up to 40 days under conditions of stable down-regulation of adipophilin and/or TIP47. RESULTS: Whereas perilipin and adipophilin were expressed in human chronic liver disease irrespective of the underlying etiology, in acute/microvesicular steatosis TIP47, and MLDP were recruited from the cytoplasm to LDs, adipophilin was strongly increased, but perilipin was virtually absent. In long-term steatosis models in vitro, TIP47, MLDP, adipophilin, and finally perilipin were gradually induced. Perilipin and associated formation of LDs were intricately regulated on the transcriptional (PPARs, C/EBPs, SREBP), post-transcriptional, and post-translational level (TAG-amount, LD-fusion, phosphorylation-dependent lipolysis). In long-term steatosis models under stable down-regulation of adipophilin and/or TIP47, MLDP substituted for TIP47, and perilipin for adipophilin. CONCLUSIONS: LD-maturation in hepatocytes in vivo and in vitro involves sequential expression of TIP47, MLDP, adipophilin and finally perilipin. Thus, perilipin might be used for the differential diagnosis of chronic vs. acute steatosis.

Adipophilin/perilipin-2 as a lipid droplet-specific marker for metabolically active cells and diseases associated with metabolic dysregulation.

AIMS: Lipid droplets (LDs) are dynamic storage compartments for energy-rich fats that are nearly ubiquitously present in eukaryotic cells, exerting tissue-specific functions in metabolically active cell types, and are increased in conditions following cellular damage or lipid overload. The LD-cytoplasm interface is stabilized by amphiphilic proteins of the PAT/perilipin family (perilipin/perilipin-1, adipophilin/perilipin-2, and TIP47/perilipin-3). We evaluated the value of adipophilin immunohistochemistry for the diagnosis of diseases associated with LD accumulation. METHODS AND RESULTS: In human tissues, adipophilin-positive LDs were especially prominent in steroidogenic cells of the adrenal gland, testis, and ovary, in hepatocytes and hepatic stellate cells, in cardiac, striated and smooth myocytes, in lactating mammary gland epithelial cells, and in plurivacuolar adipocytes. Variable amounts of adipophilin-positive LDs were also detected almost ubiquitously in epithelial cells of the gastrointestinal tract and skin. In diseases associated with lipid storage, adipophilin was strongly expressed in lipid-laden macrophages in atherosclerosis, in cardiomyopathies, kidney diseases, hepatocyte steatosis, colon ischaemia, and at the border of organ infarcts. CONCLUSIONS: Adipophilin immunohistochemistry visualizes small LDs in tissues under physiological and disease conditions that are not visible by conventional light microscopy. Immunohistology for adipophilin may facilitate histomorphological diagnosis of diseases and definition of the extent of metabolic dysregulation, such as in organ infarcts, cardiomyopathies, kidney diseases, and microvesicular steatosis.