A Cell-type-resolved Liver Proteome

Abstract

Parenchymatous organs consist of multiple cell types, primarily defined as parenchymal cells (PCs) and nonparenchymal cells (NPCs). The cellular characteristics of these organs are not well understood. Proteomic studies facilitate the resolution of the molecular details of different cell types in organs. These studies have significantly extended our knowledge about organogenesis and organ cellular composition. Here, we present an atlas of the cell-type-resolved liver proteome. In-depth proteomics identified 6000 to 8000 gene products (GPs) for each cell type and a total of 10,075 GPs for four cell types. This data set revealed features of the cellular composition of the liver: (1) hepatocytes (PCs) express the least GPs, have a unique but highly homogenous proteome pattern, and execute fundamental liver functions; (2) the division of labor among PCs and NPCs follows a model in which PCs make the main components of pathways, but NPCs trigger the pathways; and (3) crosstalk among NPCs and PCs maintains the PC phenotype. This study presents the liver proteome at cell resolution, serving as a research model for dissecting the cell type constitution and organ features at the molecular level.

Interspecies NASH disease activity whole-genome profiling identifies a fibrogenic role of PPARα-regulated dermatopontin

“…The tissue-specific distribution of Dpt was assessed in several mouse tissues ( Figure 2D), showing a predominant expression in adipose tissues, skin, and lungs, as previously reported in tissue atlas expression studies (http://biogps.org/#goto=genereport&id=1805). Dpt expression in the liver was low but detectable, but was strongly enriched (more than 800-fold) in purified HSCS (Figure 2E), in line with proteomic and RNA-seq data (42,43). In agreement with our predictions ( Figure 2C), Dpt expression was inducible by TGFβ in the human stellate LX2 cell line ( Figure 2F).…”

“…DPT was identified as an potential novel component of the liver fibrotic response that is specifically expressed in HSC (Figure 2; refs. 42,43). Our combined analysis, as well as a more limited study (68), demonstrated DPT upregulation in the liver of NASH patients.…”

“…Of note, 20 of the 34 upregulated genes display cell-specific expression in normal mouse liver, 8 of them being strongly expressed in HSCs (Figure 2A; refs. 42,43).…”

Quantitative Analysis of the Whole-Body Metabolic Fate of Branched-Chain Amino Acids

“…Dietary BCAAs are initially taken up with other nutrients by the intestine, but, unlike other amino acids, a majority of BCAAs bypass ''firstpass'' hepatic metabolism, likely in part due to the relatively low transamination activity of hepatocytes in the liver (Hutson et al, 1992). Some transamination likely does occur in the liver, as BCAT is present in non-hepatocyte cells in the liver (Ding et al, 2016), but how much is not clear. Extrahepatic tissues transaminate most BCAAs and can return their cognate alpha-ketoacids to the liver for oxidation by BCKDH (Goodwin et al, 1998;Shin et al, 2014).…”

Identification and validation of alternative splicing isoforms as novel biomarker candidates in hepatocellular carcinoma

“…AS of pre-mRNA enables a gene to produce multiple protein isoforms, usually with distinct functions. This mechanism generates transcriptomic and proteomic diversity in different tissues and cell types (4,5), however, in some disease states, for example in cancerous conditions, the damaged or diseased cells take this advantage to produce aberrant protein isoforms that contribute to tumorigenesis (6).…”