Elafin inhibits obesity, hyperglycemia, and liver steatosis in high-fat diet-treated male mice

Abstract

Elafin is an antimicrobial and anti-inflammatory protein. We hypothesize that elafin expression correlates with diabetes. Among non-diabetic and prediabetic groups, men have significantly higher serum elafin levels than women. Men with type 2 diabetes mellitus (T2DM) have significantly lower serum elafin levels than men without T2DM. Serum elafin levels are inversely correlated with fasting blood glucose and hemoglobin A1c levels in men with T2DM, but not women with T2DM. Lentiviral elafin overexpression inhibited obesity, hyperglycemia, and liver steatosis in high-fat diet (HFD)-treated male mice. Elafin-overexpressing HFD-treated male mice had increased serum leptin levels, and serum exosomal miR181b-5p and miR219-5p expression. Transplantation of splenocytes and serum exosomes from elafin-overexpressing HFD-treated donor mice reduced food consumption and fat mass, and increased adipose tissue leptin mRNA expression in HFD-treated recipient mice. Elafin improved leptin sensitivity via reduced interferon-gamma expression and induced adipose leptin expression via increased miR181b-5p and miR219-5p expression. Subcutaneous and oral administration of modified elafin inhibited obesity, hyperglycemia, and liver steatosis in the HFD-treated mice. Circulating elafin levels are associated with hyperglycemia in men with T2DM. Elafin, via immune-derived miRNAs and cytokine, activates leptin sensitivity and expression that subsequently inhibit food consumption, obesity, hyperglycemia, and liver steatosis in HFD-treated male mice.

Role of Neutrophils in the Pathogenesis of Nonalcoholic Steatohepatitis

“…Elafin is an antimicrobial and anti-inflammatory protein with a molecular weight of approximately 6 kDa ( 205 ). Lentiviral overexpression of elafin inhibits HFD-induced steatosis in mice ( 206 ). MPO has also been studied as a target of anti-neutrophil therapies because it mediates multiple steps in neutrophil-induced inflammation and tissue damage ( 207 ).…”

Elafin Reverses Intestinal Fibrosis by Inhibiting Cathepsin S-Mediated Protease-Activated Receptor 2

“…56 It is unfeasible to define phenotype-based therapy in current clinical practice because most CD patients' phenotypes are unknown. We believe that the elafin-Eudragit FS30D formulation can cover intestinal inflammation and fibrosis because the same formulation inhibited obesity and hyperglycemia in high-fat diet-treated mice, 22 which had lowgrade chronic intestinal inflammation. 57 In summary, elafin inhibits cathepsin S-dependent PAR2 activity and reduces ZEB1 and collagen expression in intestinal fibroblasts.…”

“…8,21 Oral elafin formulation was as efficacious as lentiviral elafin overexpression in reversing obesity and diabetes in high-fat diet-treated mice. 22 Intravenous infusion of elafin to increase circulating levels (4.5 mg/mL) is also safe without affecting plasma elastase activity and cytokine levels in patients. 23 Therefore, elafin is an attractive therapeutic target against intestinal inflammation and fibrosis.…”

“…We generated a clinically relevant elafin-Eudragithydroxypropyl methylcellulose (HPMC) formulation for oral administration (Figure 15A). 22 Oral elafin-Eudragit- (A) Serum-starved CD-HIF were transfected with either control or ZEB1-overexpressing construct via lipofectamine 3000 overnight. Fibroblasts were then pretreated with 100 mg/mL CDSE.…”

Roles and mechanisms of exosomal non-coding RNAs in human health and diseases

“… 366 Elsewhere, exosomal miR181b‑5p and miR219‑5p of immune cell origin that are induced by elafin (an anti-inflammatory protein) promote leptin expression in adipocytes to reduce food consumption, obesity, and hyperglycemia in HFD male mice. 378 It has been reported that aerobic exercise regulates serum exosomal miRNAs in obese mice. It decreases the levels of miR-122, miR-192, and miR-22, which are associated with improved adipogenesis, insulin sensitivity, and hepatic steatosis.…”