Hepatic Meteorin-like and Krüppel-like Factor 3 are Associated with Weight Loss and Liver Injury

Abstract

Objective Laparoscopic adjustable gastric banding (LAGB) was found to be effective in reducing body weight and improving insulin resistance in patients with obesity and non-alcoholic fatty liver disease (NAFLD). The adipokine/myokine meteorin-like (METNRL) is an important regulator of whole-body energy expenditure. Krüppel-like factor 3 (KLF3), a regulator of METRNL expression in eosinophils, inhibits the beiging of adipose tissue in mice and therefore regulates adipose tissue development. Methods Thirty-three obese patients undergoing LAGB were included in the study. The hepatic and adipose tissue expression of METNRL and KLF3 was determined before (t0) and 6 months after (t6) LABG. The human liver cancer cell line (HepG2) was stimulated with cytokines and fatty acids and METNRL and KLF3 expressions were analyzed. Results LAGB-associated weight loss was correlated with decreased hepatic METNRL expression. The expression of METNRL and KLF3 in hepatic-and adipose tissues correlated before and after LAGB. Individuals with augmented LAGB-induced weight loss (>20 kg) showed lower hepatic METNRL and KLF3 expression before and after LAGB than patients with <20 kg weight loss. METNRL and KLF3 levels were higher in patients with higher NAFLD activity scores. HepG2 stimulation with interleukin-1β, tumor necrosis factor-α, palmitic acid but not interleukin-6, oleic acid, or lipopolysaccharide, induced the expression of one or both investigated adipokines. Conclusions The novel description of METRNL and KLF3 as hepatokines could pave the way to target their production and/or signaling in obesity, NAFLD, and related disorders. Both proteins may act as possible biomarkers to estimate weight loss after bariatric surgery.

Organokines and liver enzymes in adolescent girls with polycystic ovary syndrome during randomized treatments

“…This finding is somewhat unexpected, as METRNL, previously considered mostly an adipokine and myokine, has been proposed to play a protective role against insulin resistance and inflammation in experimental models of obesity ( 43 ), and is usually downregulated in adult patients with obesity ( 44 ). However, our findings are consistent with a recent report pointing to METRNL as a hepatokine specifically induced by hepatic injury in obese patients ( 30 ). Considering the aforementioned positive role of METRNL in systemic metabolism, our results suggest enhanced METRNL synthesis in OC-treated girls as a reaction to the hepatic changes elicited by OC treatment.…”

“…findings are consistent with a recent report pointing to METRNL as a hepatokine specifically induced by hepatic injury in obese patients (30). Considering the aforementioned positive role of METRNL in systemic metabolism, our results suggest enhanced METRNL synthesis in OC-treated girls as a reaction to the hepatic changes elicited by OC treatment.…”

“…To our knowledge, this is the first study in PCOS adolescents exploring the effects of two randomized treatments on the circulating concentrations of DBI, a multifunctional protein that mediates broad hepatoprotective effects ( 41 ), and METRNL, a regulatory protein involved in adipose tissue plasticity, inflammation, and cardiac function ( 42 ), recently identified as a potential hepatokine ( 30 ). DBI levels were lower in OC-treated patients than in spiomet-treated patients, but showed no correlation with indicators of hepatic damage.…”

“…Existing knowledge on the identity and role of organokines connecting MAFLD hepatic disturbances with systemic metabolic and cardiovascular diseases is still limited, and there are a number of recently recognized circulating molecules that potentially play this role. We chose to analyze the effects of OCs vs spiomet on organokines recently related to MAFLD, such as meteorin-like protein (METRNL), recently reported to be related to liver injury ( 30 ); fibroblast growth factor-21 (FGF21), a hepatokine with enhanced expression in liver disease, potentially protective against systemic dysmetabolism in MALFD ( 31 ), and diazepam-binding protein-1 (DBI, also named acyl CoA-binding protein), whose blockage has been reported to improve MAFLD in recent experimental settings ( 32 ). We described their associations with circulating biomarkers of hepatic damage, which were assessed longitudinally in the aforementioned studies as safety markers ( 19 , 20 ).…”

Serum Metrnl is Decreased in Metabolic Dysfunction-Associated Fatty Liver Disease: A Case-Control Study

“…Findings from an Australian team indicate that hepatic Metrnl expression of obese patients decrease after bariatric surgery. 30 Via the rigorous case-control study, we elucidate that serum Metrnl decreases in patients with MAFLD and negatively correlates with the prevalence of MAFLD, even after adjustment for common risk factors of MAFLD such as WC, FG, blood pressure, γ-GGT, etc. Our data suggest circulating Metrnl might be a protective factor of MAFLD.…”