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Hepatocellular steatosis constitutes the most frequent liver disease in western countries and may progress to steatohepatitis, liver cirrhosis and hepatocellular carcinoma (HCC). The lipid droplet (LD)-associated proteins perilipin, adipophilin, TIP47 ("tail interacting protein of 47 kDa"), S3-12 and myocardial LD protein (MLDP), so-called perilipins 1-5 (PAT family) govern formation, maintenance and degradation of LDs. A lack of perilipin in mice inhibits obesity and a lack of adipophilin or TIP47 inhibit the development of fatty liver disease. In long-term cell culture models as well as in liver biopsies of patients with different acute and chronic liver diseases, LD-associated proteins are sequentially recruited to LDs and regulated via peroxisome proliferator-activated receptor (PPAR) α and PPARγ as well as posttranscriptionally via alternative splicing, LD fusion and lipolysis. Whereas TIP47 and MLDP coat small newly formed LDs in acute microvesicular steatosis, adipophilin constitutes a robust general marker for LDs in many different cell types. Perilipin is important for the long-term storage of lipids in macrovesicular steatosis and controls lipolysis via hormone-dependent phosphorylation. During malignant transformation, increased formation of small LDs and overexpression of adipophilin, TIP47 and MLDP are detected, possibly as the expression of an altered tumor metabolism analogous to a Warburg effect. Adipophilin correlates positively with the proliferation rate of HCC cells. Cultured cells with downregulation of TIP47 or adipophilin via small interfering RNA (siRNA) or small hairpin RNA (shRNA) show less but larger LDs with reduced neutral fat content.

Background: The accumulation of hepatocellular lipid droplets, referred to as steatosis, is the most frequent liver pathology in western industrial countries. The surface of lipid droplets is stabilized by amphiphilic proteins of the PAT family (perilipin, adipophilin, TIP47). We recently showed that PAT proteins are differentially expressed in liver., Methods: The effects of lipid droplet induction with oleate and of siRNA-mediated downregulation of PAT proteins were evaluated using immunofluorescence microscopy, immunoblot and functional assays., Results: Whereas perilipin, adipophilin and (in only minor amounts) also TIP47 coat lipid droplets in steatotic hepatocytes, adipophilin and TIP47, but not perilipin, are detectable in hepatocellular cell cultures. Likewise, perilipin is not induced after downregulation of adipophilin and TIP47., Conclusions: Common cell culture models show specific differences to human hepatocyte steatosis in vivo. Perilipin may play a role in the long-term storage of fat, which may be only partially reflected by cell culture models.

Genomewide association studies (GWAS) are being reported for an increasing number of common diseases, including first reports on GWAS for hepatobiliary diseases. Most common liver diseases are multifactorial (complex) diseases that are modified by higher-order interactions between multiple genetic and environmental risk factors. The aim of GWAS is to identify the genetic risk factors contributing to disease susceptibility and/or progression. In GWAS, large patient cohorts are genotyped for genetic markers that cover the whole genome, and genotypes are associated with phenotypes by contingency tests and regression analyses. Recent GWAS have identified "risk genes" for gallstones, fatty liver, primary cholestatic liver diseases and chronic hepatitis C virus (HCV) infection as well as fibrosis progression in HCV-infected patients. For the latter patients, "gene signatures" were developed that are composed of multiple risk variants and are associated with progressive liver fibrosis. Furthermore, mouse models are an important tool to identify novel genetic determinants of complex liver diseases. In large experimental crosses of susceptible and resistant inbred mouse strains, phenotypes are correlated with genome-wide markers by genetic linkage analyses. The findings from genome-wide studies in mice and men may contribute to a better understanding of the pathogenesis of complex liver diseases and provide a framework for the development of "personalised" strategies for prediction, early prevention and therapy.