TY - JOUR
T1 - Hepatic transcriptome signatures in patients with varying degrees of nonalcoholic fatty liver disease compared with healthy normal-weight individuals
AU - Suppli, Malte P
AU - Rigbolt, Kristoffer T G
AU - Veidal, Sanne S
AU - Heebøl, Sara
AU - Lykke Eriksen, Peter
AU - Demant, Mia
AU - Bagger, Jonatan I
AU - Nielsen, Jens Christian
AU - Oró, Denise
AU - Thrane, Sebastian W
AU - Lund, Asger
AU - Strandberg, Charlotte
AU - Kønig, Merete J
AU - Vilsbøll, Tina
AU - Vrang, Niels
AU - Thomsen, Karen Louise
AU - Grønbæk, Henning
AU - Jelsing, Jacob
AU - Hansen, Henrik H
AU - Knop, Filip K
PY - 2019/4/1
Y1 - 2019/4/1
N2 - Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of conditions ranging from simple steatosis (NAFL), over non-alcoholic steatohepatitis (NASH) with or without fibrosis, to cirrhosis with end-stage disease. The hepatic molecular events underlying the development of NAFLD and transition to NASH are poorly understood. The present study aimed to determine hepatic transcriptome dynamics in patients with NAFL or NASH compared to healthy normal-weight and obese individuals. RNA sequencing and quantitative histomorphometry of liver fat, inflammation and fibrosis was performed on liver biopsies obtained from healthy normal weight (n=14) and obese (n=12) individuals, NAFL (n=15) and NASH (n=16) patients. Normal weight and obese subjects showed normal liver histology and comparable gene expression profiles. Liver transcriptome signatures were largely overlapping in NAFL and NASH patients, however, clearly separated from healthy normal-weight and obese controls. Most marked pathway perturbations identified in both NAFL and NASH were associated with markers of lipid metabolism, immunomodulation, extracellular matrix remodeling and cell cycle control. Interestingly, NASH patients with positive Sonic hedgehog hepatocyte staining showed distinct transcriptome and histomorphometric changes compared to NAFL. In conclusion, application of immunohistochemical markers of hepatocyte injury may serve as a more objective tool for distinguishing NASH from NAFL, facilitating improved resolution of hepatic molecular changes associated with progression of NAFLD.
AB - Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of conditions ranging from simple steatosis (NAFL), over non-alcoholic steatohepatitis (NASH) with or without fibrosis, to cirrhosis with end-stage disease. The hepatic molecular events underlying the development of NAFLD and transition to NASH are poorly understood. The present study aimed to determine hepatic transcriptome dynamics in patients with NAFL or NASH compared to healthy normal-weight and obese individuals. RNA sequencing and quantitative histomorphometry of liver fat, inflammation and fibrosis was performed on liver biopsies obtained from healthy normal weight (n=14) and obese (n=12) individuals, NAFL (n=15) and NASH (n=16) patients. Normal weight and obese subjects showed normal liver histology and comparable gene expression profiles. Liver transcriptome signatures were largely overlapping in NAFL and NASH patients, however, clearly separated from healthy normal-weight and obese controls. Most marked pathway perturbations identified in both NAFL and NASH were associated with markers of lipid metabolism, immunomodulation, extracellular matrix remodeling and cell cycle control. Interestingly, NASH patients with positive Sonic hedgehog hepatocyte staining showed distinct transcriptome and histomorphometric changes compared to NAFL. In conclusion, application of immunohistochemical markers of hepatocyte injury may serve as a more objective tool for distinguishing NASH from NAFL, facilitating improved resolution of hepatic molecular changes associated with progression of NAFLD.
KW - Histomorphometry
KW - Nonalcoholic fatty liver disease
KW - Nonalcoholic steatohepatitis
KW - Transcriptomics
UR - http://www.scopus.com/inward/record.url?scp=85062963205&partnerID=8YFLogxK
U2 - 10.1152/ajpgi.00358.2018
DO - 10.1152/ajpgi.00358.2018
M3 - Journal article
C2 - 30653341
SN - 0193-1857
VL - 316
SP - 462
EP - 472
JO - American Journal of Physiology: Gastrointestinal and Liver Physiology
JF - American Journal of Physiology: Gastrointestinal and Liver Physiology
IS - 4
ER -