Exploration of global gene expression in human liver steatosis by high-density oligonucleotide microarray

Abstract

Understanding the molecular mechanisms underlying fatty liver disease (FLD) in humans is of major importance. We used high-density oligonucleotide microarrays (22.3 K) to assess the mechanisms responsible for the development of human liver steatosis. We compared global gene expression in normal (n ¼ 9) and steatotic (n ¼ 9) livers without histological signs of inflammation or fibrosis. A total of 34 additional human samples including normal (n ¼ 11), steatosis (n ¼ 11), HCV-related steatosis (n ¼ 4) or steatohepatitis associated with alcohol consumption (n ¼ 4) or obesity (n ¼ 4) were used for immunohistochemistry or quantitative realtime PCR studies. With unsupervised classification (no gene selection), all steatotic liver samples clustered together. Using step-down maxT multiple testing procedure for controlling the Family-Wise Error-Rate at level 5%, 110 cDNAs (100 over-and 10 underexpressed) were found to be differentially expressed in steatotic and normal livers. Of them were genes involved in mitochondrial phosphorylative and oxidative metabolism. The mean ratio of mitochondrial DNA to nuclear DNA content was higher in liver steatosis compared to normal liver biopsies (1.1270.14 vs 0.6770.10; P ¼ 0.01). An increased expression of genes involved in inflammation (IL-1R family, TGFB) was also observed and confirmed by quantitative RT-PCR or immunochemistry. In steatohepatitis, an increase of the protein expression of mitochondrial antigens, IL-1R1, IGF2 and TGFB1 was also observed, interleukin 1 receptor being always strongly expressed in steatohepatitis linked to alcohol or obesity. In conclusion, mitochondrial alterations play a major role in the development of steatosis per se. Activation of inflammatory pathways is present at a very early stage of steatosis, even if no morphological sign of inflammation is observed. Laboratory Investigation (2006) 86, 154-165.

Genes Involved in Fatty Acid Partitioning and Binding, Lipolysis, Monocyte/Macrophage Recruitment, and Inflammation Are Overexpressed in the Human Fatty Liver of Insulin-Resistant Subjects

“…Results regarding differences between subjects with and without steatosis were not reported. Chiappini et al (19) recently reported microarray data comparing hepatic gene expression between obese steatotic (n ϭ 9) and significantly leaner subjects. Features of insulin resistance or degree of alcohol consumption were not reported.…”

Differential Expression of Oxidative Stress and Inflammation Related Genes in Peripheral Blood Mononuclear Cells in Response to a Low-Calorie Diet: A Nutrigenomics Study

“…Molecular mechanisms underlying several human diseases have been investigated by gene expression analysis of peripheral blood mononuclear cells (PBMC) as surrogates for predicting potential effects in tissues that are not easily accessible (Eady et al, 2005). These cells have been proposed as a useful tool to better understand multiple sclerosis related pathways (Achiron and Gurevich, 2006), the pathophysiology of Alzheimer's disease (Maes et al, 2006), hepatic diseases (Chiappini et al, 2006;Patalay et al, 2005), oncology (DePrimo et al, 2003;Twine et al, 2003), and cardiovascular research (Horwitz et al, 2004). Also, peripheral blood mononuclear cells (PBMC) were suggested as a surrogate tissue to muscle biopsies to study mitochondrial dysfunction (Abu-Amero and Bosley, 2005;Marriage et al, 2003).…”

Hepatic steatosis, body mass index and long term outcome in patients undergoing hepatectomy for colorectal liver metastases

“…Hepatic steatosis is a histopathological state in which there is infiltration and excessive accumulation of lipids within hepatocytes (1) . The true incidence of hepatic steatosis remains unknown, however it has been reported that 34% of adult Americans have hepatic steatosis as detected by magnetic resonance spectroscopy (2) , increasing to 93% in severely obese subjects in one recent case series study (3) .…”