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Mammoth data set from human liver reported A consortium of researchers report in JPR (2009, DOI 10.1021/pr900532r) their initial analysis of the human liver proteome, having assembled the largest proteomics data set yet for a human organ. The expression data has been compiled into two databases: Human Liver Expression Profile (dbLEP; http://dblep.hupo.org.cn) and Liverbase (http://liverbase.hupo.org.cn). The liver plays multiple essential roles in physiologysit produces digestive enzymes, hormones, and most of the proteins in the blood, and it stores glycogen and breaks down drugs. Project chairman Fuchu He at the State Key Laboratory of Proteomics, Beijing Proteome Research Center, and the Beijing Institute of Radiation Medicine says that investigating liver proteins is especially important for Chinese medicine because of the prevalence of hepatitis and liver cancer in China. The Human Liver Proteome Project (HLPP) was launched in 2002 as the first project of the Human Proteome Initiative for human organs and tissues, and also one of the first international collaborations in the life sciences to be led by China. As a close alliance with HLPP, the overall program of the Chinese Human Liver Proteome Project was initiated in 2004 by the Ministry of Science and Technology. Eleven laboratories were involved in a subproject devoted to expression profiling. Tissue samples were obtained from 10 adult volunteers undergoing surgery for hepatic hemangioma (a benign tumor of blood vessels) in 2005. The researchers used four standard techniques to separate either digested peptides or whole proteins before identifying them via MS. Each approach was duplicated at two of the participating centers, and each method was duplicated at least three times. A total of 6788 proteins were identified, though that number excludes >6000 proteins that had only one peptide match and were eliminated from the final count. The researchers identified proteins corresponding to ∼60% of all of the protein-encoding genes expressed in
10.1021/pr9007464
liver, which were identified by RNA analysis from the same samples. Proteins involved in liver-specific functions, such as bile transport, bile acid synthesis, and bilirubin metabolism, were well-represented in the liver proteome. Also heavily represented were proteins involved in metabolism, nutrient transport, and blood coagulation, as well as comple-
Liver as transportation hub. Proteins involved in nutrient transport are well-represented in the liver proteome.
ment proteins. In the signal transduction realm, the liver was well-covered in areas such as MAP kinase pathways, calcium, adhesion, insulin, and adipocytokine signaling, but low in other parts. Some 3721 of the identified proteins had not been seen in human liver before, though they had been detected in other human organs. Almost 1000 were “hypothetical”stheir existence previously inferred from DNA sequence information only. Most (82.5%) of the newly identified liver proteins are present in low abundance. An intriguing finding is that many of the newly identified proteins appear to be related to pathological processes in the nervous system, according to the authors’ analysis using the Kyoto Encyclopedia of Genes and Genomes database. Humans have 57 members of the cytochrome p450 enzyme family, which are critical for metabolizing and activating drugs. Of these, the liver proteome
© 2010 American Chemical Society
team identified 31, and 4 were seen for the first time in human liver. About one-quarter of the members of the cytochrome p450 family are devoted to steroid hormones, and another chunk is involved in handling prostaglandins and fat-soluble vitamins, says Frederick Guengerich, director of molecular toxicology at the Vanderbilt University School of Medicine. “So you wouldn’t expect all of those to be expressed in the liver, but rather in the adrenals, the ovaries, and other endocrine organs,” he says. “Seeing 31 family members in the liver seems like reasonably good coverage.” Similarly, three ion-channel proteins, which tend to be low-abundance and difficult to extract, were seen for the first time in human liver by the liver proteome team. “It’s a very comprehensive baseline,” says Anand Mehta, who studies liver cancer biomarkers at the Drexel University College of Medicine. Groups such as his have performed comparisons of normal liver and diseased liver previously, “but this kind of breadth of coverage has not been achieved before.” Mehta expressed some concern that the volunteers’ hemangiomas may have had some distorting effect on the “normal liver” proteins, but he says the effects should become more apparent as more comparisons between normal and diseased states are conducted. Project coordinator Junjie Zheng, an assistant to He, says the team plans to refine its protein separation and analysis techniques. “From a technological perspective, the quality of this proteome will be improved by the development of higher-performance methods of protein separation, more sensitive and accurate methods of protein identification, and advances in data mining,” he says. “Ultimately, the proteomes of the individual cell types that make up the liver, as well as their organelles, will be profiled.” In addition, follow-up work with different developmental stages and comparisons of normal liver versus liver affected by diseases such as hepatitis B, fibrosis, cirrhosis, or hepatocellular carcinoma are also in progress, he says. —Quinn Martin Eastman
Journal of Proteome Research • Vol. 9, No. 1, 2010 3
