Increased Secreted Frizzled-Related Protein 5 mRNA Expression in the Adipose Tissue of Women with Nonalcoholic Fatty Liver Disease Associated with Obesity

Abstract

Secreted frizzled-related protein 5 (SFRP5) is an anti-inflammatory adipocytokine secreted by adipocytes that seems to be linked with nonalcoholic fatty liver disease (NAFLD). We aimed to evaluate the role of the SFRP5-wingless-MMTV integration site family member 5a (WNT5A) pathway, closely related to adipogenesis, in subcutaneous (SAT) and visceral adipose tissues (VAT) and its relationship with obesity-related NAFLD. Our cohort was composed of 60 women with morbid obesity (MO), who underwent hypocaloric diet, subclassified according to their hepatic histopathology and 15 women with normal weight. We observed increased SFRP5 mRNA expression in VAT and lower WNT5A expression in SAT in MO compared to normal weight. We found elevated SFRP5 expression in nonalcoholic steatohepatitis (NASH) in SAT and in mild simple steatosis (SS) and NASH in VAT. We observed higher WNT5A expression in SS compared to normal liver in SAT, and a peak of WNT5A expression in mild SS. To conclude, we reported increased SFRP5 mRNA expression in SAT and VAT of NAFLD-related to obesity subjects, suggesting an implication of the SFRP5-WNT5A pathway in NAFLD pathogenesis, probably due to the adipose tissue-liver axis. Since the mechanisms by which this potential interaction takes place remain elusive, more research in this field is needed.

Keywords: adipose tissue-liver axis; non-alcoholic fatty liver disease; obesity; secreted frizzled-related protein 5.

Figure 1

Obesity, the main comorbidity of NAFLD [2,5,6], causes chronic low-grade inflammation of the adipose tissue, leading to an upregulation of WNT5A [27,28] and a decrease in SFRP5 [26]. In mesenchymal stromal cells, WNT5A inhibits the adipogenesis by blocking PPARγ [21]. In mature adipocytes, WNT5A triggers an inflammatory response, lipogenic outcomes and insulin resistance [23,29,30], while PPARγ exhibits anti-inflammatory properties and acts as an insulin sensitizer [31,32]. These signs of metabolic breakdown could negatively affect the liver, making it susceptible to NAFLD occurrence [33,34]. NAFLD, nonalcoholic fatty liver disease; SFRP5, secreted frizzled-related protein 5; WNT, wingless-MMTV integration site; WNT5A, WNT family member 5a; PPARγ, peroxisome proliferator-activated receptor gamma.

Figure 2

Differential relative mRNA abundance of SFRP5, WNT5A and PPARγ in subcutaneous and visceral adipose tissue of the entire unclassified cohort. The data were normalized by NW group and expressed as mean standard error of the mean (SEM). SAT, subcutaneous adipose tissue; VAT, visceral adipose tissue; SFRP5, secreted frizzled-related protein 5; WNT5A, WNT family member 5a; PPARγ, peroxisome proliferator-activated receptor gamma; A.U arbitrary units. p < 0.05 was considered statistically significant (bold).

Figure 3

Differential relative mRNA abundance of (A) SFRP5, (C) WNT5A and (E) PPARγ in subcutaneous adipose tissue and (B) SFRP5, (D) WNT5A and (F) PPARγ in visceral adipose tissue of women classified depending on their BMI in NW and MO. The data were normalized by NW group and expressed as mean standard error of the mean (SEM). SAT, subcutaneous adipose tissue; VAT, visceral adipose tissue; SFRP5, secreted frizzled-related protein 5; WNT5A, WNT family member 5a; PPARγ, peroxisome proliferator-activated receptor gamma; NW, normal weight; MO, morbid obesity; A.U arbitrary units. p < 0.05 was considered statistically significant (bold).

Figure 4

Differential relative mRNA abundance of (A) SFRP5, (C) WNT5A and (E) PPARγ in subcutaneous adipose tissue and (B) SFRP5, (D) WNT5A and (F) PPARγ in visceral adipose tissue of women with MO classified depending on NAFLD presence into NL or NAFLD. The data were normalized by NL group and expressed as mean standard error of the mean (SEM). SAT, subcutaneous adipose tissue; VAT, visceral adipose tissue; SFRP5, secreted frizzled-related protein 5; WNT5A, WNT family member 5a; PPARγ, peroxisome proliferator-activated receptor gamma; NW, normal weight; MO, morbid obesity; A.U arbitrary units. p < 0.05 was considered statistically significant (bold).

Figure 5

Differential relative mRNA abundance of (A) SFRP5, (C) WNT5A and (E) PPARγ in subcutaneous adipose tissue of women with MO classified by their liver histology as NL, SS and NASH; also, differential relative mRNA abundance of (B) SFRP5, (D) WNT5A and (F) PPARγ classified as NL, mild SS, mod/sev SS, and NASH depending on the histopathological groups. The data were normalized by NL group and expressed as mean standard error of the mean (SEM). SAT, subcutaneous adipose tissue; SFRP5, secreted frizzled-related protein 5; WNT5A, WNT family member 5a; PPARγ, peroxisome proliferator-activated receptor gamma; MO, morbid obesity; SS, simple steatosis; mod/sev SS, moderate and severe SS; NASH, nonalcoholic steatohepatitis; A.U arbitrary units. p < 0.05 was considered statistically significant (bold).

Figure 6

Differential relative mRNA abundance of (A) SFRP5, (C) WNT5A and (E) PPARγ in visceral adipose tissue of women with MO classified by their liver histology as NL, SS and NASH; also, differential relative mRNA abundance of (B) SFRP5, (D) WNT5A and (F) PPARγ classified as NL, mild SS, mod/sev SS, and NASH depending on the histopathological groups. The data were normalized by NL group and expressed as mean standard error of the mean (SEM). VAT, visceral adipose tissue; SFRP5, secreted frizzled-related protein 5; WNT5A, WNT family member 5a; PPARγ, peroxisome proliferator-activated receptor gamma; MO, morbid obesity; SS, simple steatosis; mod/sev SS, moderate and severe SS; NASH, nonalcoholic steatohepatitis; A.U arbitrary units. p < 0.05 was considered statistically significant (bold).