Resolvin D1 primes the resolution process initiated by calorie restriction in obesity‐induced steatohepatitis

Abstract

Insulin resistance and nonalcoholic steatohepatitis (NASH), characterized by hepatic steatosis combined with inflammation, are major sequelae of obesity. Currently, lifestyle modification (i.e., weight loss) is the first-line therapy for NASH. However, weight loss resolves steatosis but not inflammation. In this study, we tested the ability of resolvin D1 (RvD1), an anti-inflammatory and proresolving molecule, to promote the resolution initiated by calorie restriction in obese mice with NASH. Calorie restriction reduced adipose and liver weight (-56 and -13%, respectively; P<0.001), serum leptin and resistin levels, hepatic steatosis, and insulin resistance. In addition to these, mice receiving RvD1 during the dietary intervention showed increased adiponectin expression at both the mRNA and protein levels and reduced liver macrophage infiltration (-15%, P<0.01). Moreover, RvD1 skewed macrophages from an M1- to an M2-like anti-inflammatory phenotype, induced a specific hepatic miRNA signature (i.e., miR-219-5p and miR-199a-5p), and reduced inflammatory adipokine mRNA and protein expression and macrophage innate immune response. In precision-cut liver slices (PCLSs), which override the influence of circulating factors, RvD1 attenuated hypoxia-induced mRNA and protein expression of COX-2, IL-1β, IL-6, and CCR7. Of note, RvD1 anti-inflammatory actions were absent in macrophage-depleted PCLSs. In summary, RvD1 acts as a facilitator of the hepatic resolution process by reducing the inflammatory component of obesity-induced NASH.

5-Lipoxygenase Is a Direct Target of miR-19a-3p and miR-125b-5p

“…A recent study showed that inhibition of either the BLT 1 receptor or the cysteinyl leukotriene 1 receptor decreases expression of both miRNAs in macrophages. Additionally, miR-125b-5p expression was decreased in BLT 1 2/2 mice compared with wild-type mice (12) and is upregulated by resolvin D1 (45). These observations and our data suggest a possible negative feedback regulation of 5-LO via the 5-LO products by induction of these two miRNAs.…”

Inhibition of soluble epoxide hydrolase modulates inflammation and autophagy in obese adipose tissue and liver: Role for omega-3 epoxides

“…The results of the present investigation indicate that inhibition of sEH when there is an increased content of omega-3 PUFA exerts a more favorable role in counteracting the metabolic disorders associated with obesity. In addition, our findings expand focus to include EpFA to the protective actions described for those lipid mediators derived from omega-3s through lipoxygenase-and cycloxygenase-initiated pathways (i.e., resolvins, protectins, and maresins) (16,17).…”

“…Here, we explored the metabolic effects of a sEH inhibitor (t-TUCB) in fat-1 mice with transgenic expression of an omega-3 desaturase capable of enriching tissues with endogenous omega-3 PUFA. These mice exhibited increased CYP1A1, CYP2E1, and CYP2U1 expression and abundant levels of the omega-3-derived epoxides 17,18-epoxyeicosatetraenoic acid (17, in insulinsensitive tissues, especially liver, as determined by LC-ESI-MS/MS. In obese fat-1 mice, t-TUCB raised hepatic 17,18-EEQ and 19,20-EDP levels and reinforced the omega-3-dependent reduction observed in tissue inflammation and lipid peroxidation.…”

Resolvin D1 Improves the Resolution of Inflammation via Activating NF-κB p50/p50–Mediated Cyclooxygenase-2 Expression in Acute Respiratory Distress Syndrome

“…In several studies, RvD1 has been reported to inhibit COX-2 generation to protect tissues from inflammatory injury in many diseases, such as lung injury (32) and steatohepatitis (42). Unlike COX-2 genetic deletion or pharmacological inhibition by nonsteroidal anti-inflammatory drugs, both of which result in exacerbation of inflammatory injury and impairment of recovery, RvD1 upregulated proresolving COX-2 expression in the later phase of inflammation to prompt resolution.…”