The Role of Olfactomedin 2 in the Adipose Tissue-Liver Axis and Its Implication in Obesity-Associated Nonalcoholic Fatty Liver Disease

Abstract

This study's objective was to assess the involvement of olfactomedin 2 (OLFM2), a secreted glycoprotein related to lipid metabolism regulation, in nonalcoholic fatty liver disease (NAFLD) mediated by the adipose-tissue-liver axis. OLFM2 mRNA expression was analyzed in subcutaneous (SAT) and visceral (VAT) adipose tissue by RT-qPCR. The cohort included women with normal weight (n = 16) or morbid obesity (MO, n = 60) who were subclassified into normal liver (n = 20), simple steatosis (n = 21), and nonalcoholic steatohepatitis (NASH, n = 19) groups. The results showed that OLFM2 expression in SAT was enhanced in MO individuals and in the presence of NAFLD. Specifically, OLFM2 expression in SAT was increased in mild and moderate degrees of steatosis in comparison to the absence of it. Moreover, OLFM2 expression in SAT was negatively correlated with interleukin-6 levels. On the other hand, OLFM2 expression in VAT decreased in the presence of NASH and exhibited a positive correlation with adiponectin levels. In conclusion, OLFM2 in SAT seems to be implicated in hepatic lipid accumulation. Additionally, since we previously suggested the possible implication of hepatic OLFM2 in NAFLD progression, now we propose a possible interaction between the liver and SAT, reinforcing the potential implication of this tissue in NAFLD development.

Keywords: adipose tissue; lipid metabolism; nonalcoholic fatty liver disease; olfactomedin 2.

Figure 1

Crosstalk between adipose tissue and liver. Dysfunctional adipose tissue sends FFA and adipokines through the circulation to the liver, being implicated in nonalcoholic fatty liver disease. SAT, subcutaneous adipose tissue; FFA, free fatty acids; VAT, visceral adipose tissue.

Figure 2

Comparison of mRNA abundance of OLFM2 in SAT (A) and in VAT (B) between patients with NW and MO. NW, normal weight; MO, morbid obesity; OLFM2, olfactomedin 2; VAT, visceral adipose tissue; SAT, subcutaneous adipose tissue; A.U, arbitrary units. Mann–Whitney test was used to calculate differences between groups, and p < 0.05 was considered statistically significant.

Figure 3

Differential relative mRNA expression of OLFM2 in SAT (A) and VAT (B) between patients classified according to the presence or the absence of NAFLD, and being classified by NW, NL, SS, and NASH in SAT (C) and VAT (D). OLFM2, olfactomedin 2; VAT, visceral adipose tissue; SAT, subcutaneous adipose tissue; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NW, normal weight; MO, morbid obesity; SS, simple steatosis; A.U arbitrary units. Mann–Whitney test was used to calculate differences between groups, and p < 0.05 was considered statistically significant.

Figure 4

Comparison of mRNA abundance of OLFM2 in SAT (A) and in VAT (B) samples between subjects classified into absence, mild, moderate, and severe, according to different grades of steatosis. OLFM2, olfactomedin 2; VAT, visceral adipose tissue; SAT, subcutaneous adipose tissue; A.U arbitrary units. Mann–Whitney test was used to calculate differences between groups, and p < 0.05 was considered statistically significant.

Figure 5

Comparison of mRNA expression of OLFM2 in SAT (A) and VAT (B) between absence or presence of NASH. Differential relative mRNA abundance of OLFM2 in SAT (C) and VAT (D) between absence or presence of lobular inflammation and portal inflammation absence or presence (E) in SAT and (F) in VAT. OLFM2, olfactomedin 2; VAT, visceral adipose tissue; SAT, subcutaneous adipose tissue; NASH, nonalcoholic steatohepatitis; A.U, arbitrary units. Mann–Whitney test was used to calculate differences between groups, and p < 0.05 was considered statistically significant.

Figure 6

(A) Significant negative correlations between OLFM2 mRNA expression in SAT and circulating levels of IL-6. (B) Significant positive associations between OLFM2 mRNA expression in VAT and adiponectin levels. OLFM, olfactomedin; IL, interleukin; SAT, subcutaneous adipose tissue; VAT, visceral adipose tissue; A.U, arbitrary units. The Spearman test was used to calculate the correlation coefficient (rho), and p < 0.05 was considered statistically significant.

Figure 7

Histological staining with hematoxylin and eosin (purple) and Masson’s trichrome (red) of women with (A) NW and NL, (B) MO and NL, (C) MO and SS, and (D) MO and NASH.