Inhibition of soluble epoxide hydrolase ameliorates hyperhomocysteinemia-induced hepatic steatosis by enhancing β-oxidation of fatty acid in mice

Abstract

Hepatic steatosis is the beginning phase of nonalcoholic fatty liver disease, and hyperhomocysteinemia (HHcy) is a significant risk factor. Soluble epoxide hydrolase (sEH) hydrolyzes epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids, attenuating their cardiovascular protective effects. However, the involvement of sEH in HHcy-induced hepatic steatosis is unknown. The current study aimed to explore the role of sEH in HHcy-induced lipid disorder. We fed 6-wk-old male mice a chow diet or 2% (wt/wt) high-metnionine diet for 8 wk to establish the HHcy model. A high level of homocysteine induced lipid accumulation in vivo and in vitro, which was concomitant with the increased activity and expression of sEH. Treatment with a highly selective specific sEH inhibitor (0.8 mg·kg−1·day−1 for the animal model and 1 μM for cells) prevented HHcy-induced lipid accumulation in vivo and in vitro. Inhibition of sEH activated the peroxisome proliferator-activated receptor-α (PPAR-α), as evidenced by elevated β-oxidation of fatty acids and the expression of PPAR-α target genes in HHcy-induced hepatic steatosis. In primary cultured hepatocytes, the effect of sEH inhibition on PPAR-α activation was further confirmed by a marked increase in PPAR-response element luciferase activity, which was reversed by knock down of PPAR-α. Of note, 11,12-EET ligand dependently activated PPAR-α. Thus increased sEH activity is a key determinant in the pathogenesis of HHcy-induced hepatic steatosis, and sEH inhibition could be an effective treatment for HHcy-induced hepatic steatosis. NEW & NOTEWORTHY In the current study, we demonstrated that upregulation of soluble epoxide hydrolase (sEH) is involved in the hyperhomocysteinemia (HHcy)-caused hepatic steatosis in an HHcy mouse model and in murine primary hepatocytes. Improving hepatic steatosis in HHcy mice by pharmacological inhibition of sEH to activate peroxisome proliferator-activated receptor-α was ligand dependent, and sEH could be a potential therapeutic target for the treatment of nonalcoholic fatty liver disease.

Soluble epoxide hydrolase inhibitor, TPPU, increases regulatory T cells pathway in an arthritis model

“…sEH expression increases in several diseases, 9,[20][21][22] which in turn decrease several important biological EpFAs. EET are biologically active metabolites of AA, generated by cytochrome p450s (CYP).…”

Carcinogenesis: Failure of resolution of inflammation?

“…EETs may potently downregulate endoplasmic reticulum (ER) stress responses as demonstrated in response to cigarette smoke damage ( Yu et al, 2015 ). Thus, inhibition of sEH may allow for their stability and prolonged effects and has demonstrated pro-resolution activity such as stimulation of SPMs and activating anti-cytokine programs in multiple inflammatory diseases, including those which are risk factors for cancer induction ( Schmelzer et al, 2005 ; Wang et al, 2018 ; Yao et al, 2019 ; Yu et al, 2015 ). Importantly, the sEH eicosanoid pathway has been suggested to be involved in the progression of colorectal cancer, including obesity-associated cancer ( Zhang, Sanidad, & Zhang, 2019 ).…”

Implications of hydrogen sulfide in liver pathophysiology: Mechanistic insights and therapeutic potential

“…In animal models of CBS deficiency, the enhanced oxidative stress and hepatic lipid accumulation are observed [102] . Namekata et al proposed that the abnormal metabolism in the liver from CBS knockout mice may be induced by hyperhomocysteinemia [102] , which is a risk factor for hepatic steatosis [103] . Furthermore, the same group further demonstrated that the damaged β-oxidation of fatty acid and thiolase activity, and the aberrant levels of very low density lipoprotein (VLDL) are major contributing factors for hepatic steatosis in CBS knockout mice [102] .…”