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Biological systems to sense and respond to metabolic perturbations are critical for the maintenance of cellular homeostasis. Here we describe a hepatic system in this context orchestrated by the transcriptional corepressor C-terminal binding protein 2 (CtBP2) that harbors metabolite-sensing capabilities. The repressor activity of CtBP2 is reciprocally regulated by NADH and acyl-CoAs. CtBP2 represses Forkhead box O1 (FoxO1)-mediated hepatic gluconeogenesis directly as well as Sterol Regulatory Element-Binding Protein 1 (SREBP1)-mediated lipogenesis indirectly. The activity of CtBP2 is markedly defective in obese liver reflecting the metabolic perturbations. Thus, liver-specific CtBP2 deletion promotes hepatic gluconeogenesis and accelerates the progression of steatohepatitis. Conversely, activation of CtBP2 ameliorates diabetes and hepatic steatosis in obesity. The structure-function relationships revealed in this study identify a critical structural domain called Rossmann fold, a metabolite-sensing pocket, that is susceptible to metabolic liabilities and potentially targetable for developing therapeutic approaches., (© 2021. The Author(s).)

Brown adipose tissue (BAT) is an attractive therapeutic target for treating obesity and metabolic diseases. Octacosanol is the main component of policosanol, a mixture of very long chain aliphatic alcohols obtained from plants. The current study aimed to investigate the effect of octacosanol and policosanol on high-fat diet (HFD)-induced obesity. Mice were fed on chow, or HFD, with or without octacosanol or policosanol treatment for four weeks. HFD-fed mice showed significantly higher body weight and body fat compared with chow-fed mice. However, mice fed on HFD treated with octacosanol or policosanol (HFDo/p) showed lower body weight gain, body fat gain, insulin resistance and hepatic lipid content. Lower body fat gain after octacosanol or policosanol was associated with increased BAT activity, reduced expression of genes involved in lipogenesis and cholesterol uptake in the liver, and amelioration of white adipose tissue (WAT) inflammation. Moreover, octacosanol and policosanol significantly increased the expression of Ffar4, a gene encoding polyunsaturated fatty acid receptor, which activates BAT thermogenesis. Together, these results suggest that octacosanol and policosanol ameliorate diet-induced obesity and metabolic disorders by increasing BAT activity and improving hepatic lipid metabolism. Thus, these lipids represent promising therapeutic targets for the prevention and treatment of obesity and obesity-related metabolic disorders.

Aims: Renalase expression in the kidneys and liver is regulated by nuclear factor (NF)-κB, Sp1, and hypoxia-inducible factor (HIF)-1α. The dynamics of renalase expression in acute exercise, and its mechanism and physiological effects are unclear. We evaluated the effect of different exercise intensities on renalase expression and examined its mechanism and physiological effects., Main Methods: 21 male Wistar rats ran for 30 min on a treadmill after resting for 15 min. The sedentary group rested on the treadmill while the exercise group ran for 30 min at 10 or 30 m/min. Skeletal muscles, the kidney, heart, liver, and blood samples were collected after exercise. The expression of renalase and phosphate IkB-α and Akt was measured by western blotting, while HIF-1α, Sp1, MuRF-1, and MAFbx were measured in the skeletal muscle by real-time RT-PCR., Key Findings: Renalase expression in skeletal muscles increased after acute exercise, while its expression in the kidneys, heart, and liver decreased. NF-κB regulated renalase expression in the plantaris muscle and that of HIF-1α in the soleus muscle. Phosphate Akt in the plantaris muscle significantly increased in the 30 m/min group compared with that in the sedentary group. MuRF-1 in the plantaris did not change between these groups., Significance: Renalase expression in skeletal muscles increased after acute exercise but decreased in other tissues. This increase may be a response to exercise-induced oxidative stress. Furthermore, NF-κB in the plantaris muscle may mainly regulate renalase expression, and support a relationship with the cell protective effects of renalase., (Copyright © 2018. Published by Elsevier Inc.)

The prevalence of nonalcoholic fatty liver disease (NAFLD) has been rapidly increasing worldwide. A choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) has been used to create a mouse model of nonalcoholic steatohepatitis (NASH). There are some reports on the effects on mice of being fed a CDAHFD for long periods of 1 to 3 months. However, the effect of this diet over a short period is unknown. Therefore, we examined the effect of 1-week CDAHFD feeding on the mouse liver. Feeding a CDAHFD diet for only 1-week induced lipid droplet deposition in the liver with increasing activity of liver-derived enzymes in the plasma. On the other hand, it did not induce fibrosis or cirrhosis. Additionally, it was demonstrated that CDAHFD significantly impaired mitochondrial respiration with severe oxidative stress to the liver, which is associated with a decreasing mitochondrial DNA copy number and complex proteins. In the gene expression analysis of the liver, inflammatory and oxidative stress markers were significantly increased by CDAHFD. These results demonstrated that 1 week of feeding CDAHFD to mice induces steatohepatitis with mitochondrial dysfunction and severe oxidative stress, without fibrosis, which can partially mimic the early stage of NASH in humans. [ABSTRACT FROM AUTHOR]

Progression of nonalcoholic steatohepatitis (NASH) is attributed to several factors, including inflammation and oxidative stress. In recent years, renalase has been reported to suppress oxidative stress, apoptosis and inflammation. A number of studies have suggested that renalase may be associated with protecting the liver from injury. The present study aimed to clarify the effects of renalase knockout (KO) in mice with NASH that were induced with a choline-deficient high-fat diet (CDAHFD) supplemented with 0.1% methionine. Wild type (WT) and KO mice (6-week-old) were fed a normal diet (ND) or CDAHFD for 6 weeks, followed by analysis of the blood liver function markers and liver tissues. CDAHFD intake was revealed to increase blood hepatic function markers, lipid accumulation and oxidative stress compared with ND, but no significant differences were observed between the WT and KO mice. However, in the KO-CDAHFD group, the Adgre1 and Tgfb1 mRNA levels were significantly higher, and α-SMA expression was significantly lower compared with the WT-CDAHFD group. Furthermore, the Gclc mRNA and phosphorylated protein kinase B (Akt) levels were significantly lower in the KO-ND group compared with the WT-ND group. The results of the current study indicated that as NASH progressed in the absence of renalase, oxidative stress, macrophage infiltration and TGF-β expression were enhanced, while α-SMA expression in NASH may be partly suppressed due to the decreased phosphorylation of Akt level. [ABSTRACT FROM AUTHOR]