New Insights of OLFM2 and OLFM4 in Gut-Liver Axis and Their Potential Involvement in Nonalcoholic Fatty Liver Disease

Abstract

Olfactomedins (OLFMs) are a family of glycoproteins that play a relevant role in embryonic development and in some pathological processes. Although OLFM2 is involved in the regulation of the energy metabolism and OLFM4 is an important player in inflammation, innate immunity and cancer, the role of OLFMs in NAFLD-related intestinal dysbiosis remains unknown. In this study, we analysed the hepatic mRNA expression of OLFM2 and the jejunal expression of OLFM4 in a well-established cohort of women with morbid obesity (MO), classified according to their hepatic histology into normal liver (n = 27), simple steatosis (n = 26) and nonalcoholic steatohepatitis (NASH, n = 16). Our results showed that OLFM2 hepatic mRNA was higher in NASH, in advanced degrees of steatosis and in the presence of lobular inflammation. Additionally, we obtained positive correlations between hepatic OLFM2 and glucose, cholesterol, trimethylamine N-oxide and deoxycholic acid levels and hepatic fatty acid synthase, and negative associations with weight and jejunal Toll-like receptors (TLR4) and TLR5 expression. Regarding jejunal OLFM4, we observed positive correlations with circulating interleukin (IL)-8, IL-10, IL-17 and jejunal TLR9. In conclusion, OLFM2 in the liver seems to play a relevant role in NAFLD progression, while OLFM4 in the jejunum could be involved in gut dysbiosis-related inflammatory events.

Keywords: gut-liver axis; nonalcoholic fatty liver disease; obesity; olfactomedin.

Figure 1

Differential relative mRNA abundance of OLFM2 in hepatic tissue between women with MO (A) classified as NL, SS and NASH and (B) classified according to the presence or absence of NASH. Differential relative mRNA abundance of OLFM4 in jejunal tissue between women with MO (C) classified as NL, SS and NASH and (D) classified according to the presence or absence of NASH. OLFM, olfactomedin; NL, normal liver; SS, simple steatosis; NASH, nonalcoholic steatohepatitis; A.U arbitrary units. Differences between groups were calculated using Mann–Whitney test and p < 0.05 was considered statistically significant.

Figure 2

Differential relative mRNA abundance of (A) OLFM2 in hepatic tissue and (B) OLFM4 in jejunal samples between women with MO classified according to differences grades of steatosis into absence, mild, moderate and severe. OLFM, olfactomedin. A.U arbitrary units. Differences between groups were calculated using Mann–Whitney test and p < 0.05 was considered statistically significant.

Figure 3

Differential relative mRNA abundance of hepatic OLFM2 between, (A) absence or presence of portal inflammation, (C) lobular inflammation absence or presence and (E) ballooning absence or presence. Differential relative mRNA abundance of jejunal OLFM4 between, (B) absence or presence of portal inflammation, (D) lobular inflammation absence or presence and (F) ballooning absence or presence. OLFM, olfactomedin. A.U arbitrary units. Differences between groups were calculated using Mann–Whitney test. p < 0.05 was considered statistically significant.

Figure 4

Significant correlations between OLFM2 hepatic mRNA expression and (A) glucose, (B) cholesterol (C) TMAO, (D) DCA levels and (E) FAS in liver, (F) weight, (G) jejunal TLR4 and (H) TLR5 using Spearman’s method. OLFM, olfactomedin; TMAO, Trimethylamine N-oxide dihydrate; DCA, deoxycholic acid; TLR, Toll-like receptor FAS, fatty acid synthase; RE, relative expression; A.U, arbitrary units. Correlation coefficient (rho) was calculated using Spearman test. p < 0.05 was considered statistically significant.

Figure 5

Significantly positive correlations between OLFM4 jejunal mRNA expression (A) IL-8, (B) IL-10, (C) IL-17 levels and (D) TLR9 in jejunum using Spearman’s method. OLFM, olfactomedin; TLR, Toll-like receptor; IL, interleukin; RE, relative expression; A.U, arbitrary units. Correlation coefficient (rho) was calculated using Spearman test. p < 0.05 was considered statistically significant.