Altered hepatic gene expression in nonalcoholic fatty liver disease is associated with lower hepatic n‐3 and n‐6 polyunsaturated fatty acids

Abstract

In nonalcoholic fatty liver disease, hepatic gene expression and fatty acid (FA) composition have been reported independently, but a comprehensive gene expression profiling in relation to FA composition is lacking. The aim was to assess this relationship. In a cross‐sectional study, hepatic gene expression (Illumina Microarray) was first compared among 20 patients with simple steatosis (SS), 19 with nonalcoholic steatohepatitis (NASH), and 24 healthy controls. The FA composition in hepatic total lipids was compared between SS and NASH, and associations between gene expression and FAs were examined. Gene expression differed mainly between healthy controls and patients (SS and NASH), including genes related to unsaturated FA metabolism. Twenty‐two genes were differentially expressed between NASH and SS; most of them correlated with disease severity and related more to cancer progression than to lipid metabolism. Biologically active long‐chain polyunsaturated FAs (PUFAs; eicosapentaenoic acid + docosahexaenoic acid, arachidonic acid) in hepatic total lipids were lower in NASH than in SS. This may be related to overexpression of FADS1, FADS2, and PNPLA3. The degree and direction of correlations between PUFAs and gene expression were different among SS and NASH, which may suggest that low PUFA content in NASH modulates gene expression in a different way compared with SS or, alternatively, that gene expression influences PUFA content differently depending on disease severity (SS versus NASH). Conclusion: Well‐defined subjects with either healthy liver, SS, or NASH showed distinct hepatic gene expression profiles including genes involved in unsaturated FA metabolism. In patients with NASH, hepatic PUFAs were lower and associations with gene expression were different compared to SS. (Hepatology 2015;61:1565–1578)

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

“…Unsupervised hierarchical clustering of our gene expression data did not allow a clear-cut identification of patient categories. This has already been observed in other studies (22,24,26), a pitfall probably relating to interindividual heterogeneity of the disease and the adaptive nature of the pathological response likely to trigger subtle changes in gene expression. Cohort stratification on the basis of metabolic parameters also did not identify massively dysregulated pathways.…”

“…This analysis provided no evidence for a global alteration of genes involved in these systemic metabolic functions (Supplemental Table 2), although a stratification based on BMI or HOMA-IR identified genes involved in lipid metabolism and reported to be dysregulated in NAFLD/ NASH (FASD1 and FASD2, NR0B2 and ELOVL2; refs. 22,24). In contrast, comparison of the liver transcriptomes from patients displaying different stages of hepatic histological damages with controls clearly identified functionally related clusters of genes.…”

“…To make a more stringent selection of genes involved in NASH and fibrosis progression, we assessed which genes dysregulated in our cohort could be validated in other human cohorts. Therefore, two transcriptomic studies were selected (24,27) to which similar filters (inflammation ≥ 2, fibrosis ≥ F2) and analysis methods were applied. A comparison of differentially expressed genes in all 3 cohorts, which showed similarly dysregulated biological processes (Supplemental Figure 5), generated a human NASH + fibrosis core signature containing 48 upregulated and 10 downregulated genes (Supplemental Figure 6 and Supplemental Table 7), the former being strongly enriched in genes involved in ECM formation (COL1A1 and -2, COL3A1, COL14A1, DPT, FBLN5, LUM, PDGFRA) and inflammatory responses (CCL19 and -21, CXCL9 and -10, SPP1) (Supplemental Figure 6).…”

“…Performed on cohorts stratified on the basis of more or less refined histological parameters (alcoholic steatohepatitis and NASH vs. no NASH, NASH vs. no NASH, control vs. steatosis vs. NASH, control vs. steatosis vs. NASH with steatosis > 5% vs. NASH with steatosis < 5%; refs. [22][23][24][25][26], these studies identified specific protagonists such as the Wnt pathway; genes involved in absorption, distribution, metabolism, and excretion (ADME); aldose reductase AKR1B10; and keratin family member KRT23. Comparing the liver transcriptome of NAFLD patients with no or little fibrosis to the one of fibrotic patients revealed genes involved in cellular proliferation and ECM organization (27,28).…”

Decreased Fatty Acid <i>β</i>-Oxidation Is the Main Cause of Fatty Liver Induced by Polyunsaturated Fatty Acid Deficiency in Mice

“…Related to this dietary preference, the livers of NAFLD patients contain a lower ratio of certain PUFA species, such as arachidonic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), in their total lipid extracts and triglyceride (TG) fractions compared with normal livers (Puri et al 2007). Additionally, a recent study investigating NAFLD patients including those with steatohepatitis [i.e., NASH; fatty liver with inflammation and hepatocyte ballooning (Nagaya et al 2010)] and simple steatosis [fatty liver without apparent histological features of NASH (Nagaya et al 2010)] reported that the NASH patients' livers contained a lower ratio of these PUFA species than those of the simple steatosis group, and that these PUFA profile differences were related to expression changes in several genes related to lipid metabolism (Arendt et al 2015). These findings suggest that decreasing the levels of PUFA in diets and livers and the alteration of hepatic PUFA metabolism affect the disease progression of NAFLD.…”