TY - JOUR
T1 - Cross-Species Molecular Imaging of Bile Salts and Lipids in Liver
T2 - Identification of Molecular Structural Markers in Health and Disease
AU - Flinders, Bryn
AU - Huizing, Lennart R. S.
AU - van Heerden, Marjolein
AU - Cuyckens, Filip
AU - Neumann, Ulf P.
AU - van der Laan, Luc J. W.
AU - Damink, Steven W. M. Olde
AU - Heeren, Ron M. A.
AU - Schaap, Frank G.
AU - Vreeken, Rob J.
PY - 2018/10/16
Y1 - 2018/10/16
N2 - The liver is the primary organ involved in handling of bile salts, a class of amphipathic molecules with signaling activities as well as desired and detrimental detergent actions. To allow in-depth investigation of functions of bile salts in healthy and diseased liver, the spatial distribution of bile salt species within the liver needs to be studied. Therefore, the aim of our study was to determine hepatic bile salt distribution and identify specific lipid markers that define the structural elements of the liver. Matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) was used to monitor the spatial distribution of bile salts and lipids in liver sections of rat, dog, and patients with unaffected and cholestatic parenchyma. MALDI-MSI in negative ion mode showed the local presence of a variety of bile salts, predominantly taurine-conjugates, as localized patches of varying sizes (representing the bile ducts) throughout the liver tissue. Specific molecular markers were identified for the connective tissue (phosphatidic acids, e.g., [PA (18:0_18:1)-H](-)), the liver parenchyma (phosphatidylinositols, e.g., [PI (18:0_20:4)-H](-)), and the bile ducts (hydroxylated-sulfatides, e.g., [ST-OH (18:1_24:0)-H](-)). One of these sulfatides (at m/z 906.6339) was found to be uniquely localized in a thin lining on the inside of the bile duct, colocalized with cytokeratins, and encased luminal bile salts. A similar distribution of the aforementioned sulfatide was observed, albeit in constricted ductular structures, in the liver of a patient with a mild clinical phenotype of primary sclerosing cholangitis (PSC). In contrast, sulfatides were virtually absent in the liver of patients with PSC and a severe clinical phenotype, with (atypical) cholanoids (e.g., the bile alcohol 5-cyprinolsulfate) abundant in the extra-ductular space and glyco(cheno)deoxycholic acid-3-sulfate localized to fibrotic connective tissue. The latter two molecular species were able to discriminate between healthy liver tissue (n = 3) and tissue from PSC patients with a severe clinical phenotype (n = 3). In conclusion, the distinct structural elements of the mammalian liver are characterized by specific classes of lipids. We propose that (hydroxylated-)sulfatides are specific molecular markers of the bile duct.
AB - The liver is the primary organ involved in handling of bile salts, a class of amphipathic molecules with signaling activities as well as desired and detrimental detergent actions. To allow in-depth investigation of functions of bile salts in healthy and diseased liver, the spatial distribution of bile salt species within the liver needs to be studied. Therefore, the aim of our study was to determine hepatic bile salt distribution and identify specific lipid markers that define the structural elements of the liver. Matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) was used to monitor the spatial distribution of bile salts and lipids in liver sections of rat, dog, and patients with unaffected and cholestatic parenchyma. MALDI-MSI in negative ion mode showed the local presence of a variety of bile salts, predominantly taurine-conjugates, as localized patches of varying sizes (representing the bile ducts) throughout the liver tissue. Specific molecular markers were identified for the connective tissue (phosphatidic acids, e.g., [PA (18:0_18:1)-H](-)), the liver parenchyma (phosphatidylinositols, e.g., [PI (18:0_20:4)-H](-)), and the bile ducts (hydroxylated-sulfatides, e.g., [ST-OH (18:1_24:0)-H](-)). One of these sulfatides (at m/z 906.6339) was found to be uniquely localized in a thin lining on the inside of the bile duct, colocalized with cytokeratins, and encased luminal bile salts. A similar distribution of the aforementioned sulfatide was observed, albeit in constricted ductular structures, in the liver of a patient with a mild clinical phenotype of primary sclerosing cholangitis (PSC). In contrast, sulfatides were virtually absent in the liver of patients with PSC and a severe clinical phenotype, with (atypical) cholanoids (e.g., the bile alcohol 5-cyprinolsulfate) abundant in the extra-ductular space and glyco(cheno)deoxycholic acid-3-sulfate localized to fibrotic connective tissue. The latter two molecular species were able to discriminate between healthy liver tissue (n = 3) and tissue from PSC patients with a severe clinical phenotype (n = 3). In conclusion, the distinct structural elements of the mammalian liver are characterized by specific classes of lipids. We propose that (hydroxylated-)sulfatides are specific molecular markers of the bile duct.
KW - MALDI-TOF-MS
KW - SCLEROSING CHOLANGITIS
KW - MASS-SPECTROMETRY
KW - ACIDS
KW - SULFATIDE
KW - INJURY
KW - CELLS
KW - QUANTIFICATION
KW - PATHWAYS
KW - DATASETS
U2 - 10.1021/acs.analchem.8b01378
DO - 10.1021/acs.analchem.8b01378
M3 - Article
SN - 0003-2700
VL - 90
SP - 11835
EP - 11846
JO - Analytical Chemistry
JF - Analytical Chemistry
IS - 20
ER -