Mitofusin 2 decreases intracellular lipids in macrophages by regulating peroxisome proliferator-activated receptor-γ

Mitofusin 2 (Mfn2) inhibits atherosclerotic plaque formation, but the underlying mechanism remains elusive. This study aims to reveal how Mfn2 functions in the atherosclerosis. Mfn2 expression was found to be significantly reduced in arterial atherosclerotic lesions of both mice and human compared with healthy counterparts. Here, we observed that Mfn2 increased cellular cholesterol transporter expression in macrophages by upregulating peroxisome proliferator-activated receptor-γ, an effect achieved at least partially by inhibiting extracellular signal-regulated kinase1/2 (ERK1/2) and p38 mitogen-activated protein kinases (MAPKs) pathway. These findings provide insights into potential mechanisms of Mfn2-mediated alterations in cholesterol transporter expression, which may have significant implications for the treatment of atherosclerotic heart disease.     

MicroRNA-302a inhibits adipogenesis by suppressing peroxisome proliferator-activated receptor γ expression

The present study explored the involvement of miR-302a in adipocyte differentiation via interaction with 3′-untranslated region of peroxisome proliferator-activated receptor gamma (PPARγ) mRNA. In differentiating 3T3-L1 adipocytes, expression of miR-302a was negatively correlated with that of the adipogenic gene aP2 and PPARγ. Overexpression of miR-302a inhibited adipogenic differentiation with lipid accumulation, and inversely anti-miR-302a increased the differentiation. In silico analysis revealed a complementary region of miR-302a seed sequence in 3′-UTR of PPARγ mRNA. Luciferase assay showed the direct interaction of miR-302a with PPARγ at the cellular level. The miR-302a inhibition of adipocyte differentiation was reversed by PPARγ overexpression. These findings suggest that miR-302a might be a negative regulator of adipocyte differentiation and that the dysregulation of miR-302a should lead to metabolic disorders.     

Lipid synthesis in macrophages during inflammation in vivo: Effect of agonists of peroxisome proliferator activated receptors α and γ and of retinoid X receptors

The effects of peroxisome proliferator activated receptors α and γ (PPAR-α and PPAR-γ) and retinoid X receptor (RXR) agonists upon synthesis and accumulation of lipids in murine C57B1 macrophages during inflammation induced by injection of zymosan and Escherichia coli lipopolysaccharide (LPS) have been studied. It is significant that intraperitoneal injection of zymosan (50 mg/kg) or LPS (0.1 mg/kg) in mice led to a dramatic increase of [¹⁴C]oleate incorporation into cholesteryl esters and triglycerides and [¹⁴C]acetate incorporation into cholesterol and fatty acids in peritoneal macrophages. Lipid synthesis reached its maximum rate 18–24 h after injection and was decreased 5–7 days later to control level after LPS injection or was still heightened after zymosan injection. In macrophages obtained in acute phase of inflammation (24 h), degradation of ¹²⁵I-labeled native low density lipoprotein (NLDL) was 4-fold increased and degradation of ¹²⁵I-labeled acetylated LDL (AcLDL) was 2–3-fold decreased. Addition of NLDL (50 μg/ml) or AcLDL (25 μg/ml) into the incubation medium of activated macrophages induced 9–14-and 1.25-fold increase of cholesteryl ester synthesis, respectively, compared with control. Addition of NLDL and AcLDL into the incubation medium completely inhibited cholesterol synthesis in control macrophages but had only slightly effect on cholesterol synthesis in activated macrophages. Injection of RXR, PPAR-α, or PPAR-γ agonists—9-cis-retinoic acid (5 mg/kg), bezafibrate (10 mg/kg), or rosiglitazone (10 mg/kg), respectively—30 min before zymosan or LPS injection led to significant decrease of lipid synthesis. Ten hour preincubation of activated in vivo macrophages with the abovementioned agonists (5 μM) decreased cholesteryl ester synthesis induced by NLDL and AcLDL addition into the cell cultivation medium. The data suggest that RXR, PPAR-α, or PPAR-γ agonists inhibited lipid synthesis and induction of cholesteryl ester synthesis in inflammatory macrophages caused by capture of native or modified LDL. Published in Russian in Biokhimiya, 2008, Vol. 73, No. 3, pp. 364–374.     

Diabetes: New conductors for the peroxisome proliferator-activated receptor γ (PPARγ) orchestra

The PPARγ nuclear receptor orchestrates fatty acid storage and glucose metabolism by coordinating the expression of genes involved in lipid uptake, adipogenesis and inflammation. It is a target for the insulin-sensitising thiazolidinediones (TZDs) which have been used to treat diabetes since the late nineties. Adverse secondary effects of TZDs have underpinned continued investigations into the molecular details governing PPARγ regulation and new therapeutic approaches which represent the focus of this article. Recent findings position Cdk5 as a lead conductor of PPARγ. Cdk5 regulates PPARγ directly, via phosphorylation, and may also inhibit it indirectly, via phosphorylation and activation of phospholipase D2 (PLD2) which generates the endogenous inhibitor cyclic phosphatidic acid (CPA). Whilst the multifunctional nature of Cdk5 precludes it from therapeutic targeting all is not lost as selective PPARγ modulators (SPPARMs) have shown promising preclinical and clinical results heralding a new generation of drugs to conduct a more refined PPARγ program.     

Does the lipid-lowering peroxisome proliferator-activated receptors ligand bezafibrate prevent colon cancer in patients with coronary artery disease?

Background

To investigate the clinical differences between pulse wave velocity and augmentation index in diabetic retinopathy.

Methods

The subjects were 201 patients with type 2 diabetes. These subjects were measured for both augmentation index (AI) and brachial-ankle pulse wave velocity (baPWV) by a pulse wave analyzer. The relationships between AI, baPWV, and diabetic retinopathy were examined.

Results

BaPWV was significantly higher in patients with diabetic retinopathy than in individuals without the disease. (20.13 ± 3.66 vs.17.14 ± 3.60 m/s p < 0.001) AI was higher in patients with diabetic retinopathy, but not significantly. (19.5 ± 15.2 vs. 14.8 ± 20.5% p = 0.14) The association between baPWV and diabetic retinopathy remained statistically significant after adjustment. (Odds ratio: 1.21 Per m/s, 95% confidence interval: 1.07–1.37) On the other hand, the association between AI and diabetic retinopathy was not statistically significant. (Odds ratio: 1.01 Per %, 95% confidence interval: 0.98–1.03)

Conclusion

BaPWV is associated with diabetic retinopathy, but AI is not. The clinical significance appears to be different between PWV and AI in patients with diabetes.     

The protective role of peroxisome proliferator-activated receptor γ coactivator-1α in hyperthyroid cardiac hypertrophy

Heart failure is a major cause of death throughout the world. Hyperthyroidism has been shown to induce cardiac hypertrophy, which is a contributing factor to heart failure. However, the mechanism underling effect of thyroid hormone is not completely clear. The present study investigates the role of peroxisome proliferator-activated receptor (PPAR) γ coactivator-1α (PGC-1α) in cardiac hypertrophy induced by Triiodothyronine (T3). We investigated PGC-1α mRNA expression in rat hearts exposed to T3 in vivo and ex vivo. Surprisingly, we found that the extended periods of T3 treatment led to an increase in PGC-1α expression compared to shorter treatment times, which resulted in a reduction of PGC-1α expression. Mechanistic studies showed that suppression of PGC-1α by small interfering RNA in cardiomyocytes amplified the cellular hypertrophic response to T3 stimulation, whereas overexpression of PGC-1α was protective. Furthermore, we presented evidence to show that T3 decreased PGC-1α expression via p38 mitogen-activated protein kinases (MAPK) pathway. Our studies also revealed that overexpression of PGC-1α in cardiomyocytes inhibited basal and T3-induced p38 MAPK phosphorylation. These data indicate for the first time that PGC-1α plays protective role in T3-induced cardiac hypertrophy and that hypertrophic growth induced by T3 involves a regulatory pathway between PGC-1α and p38 MAPK.     

A novel dual peroxisome proliferator-activated receptors α and γ agonist with beneficial effects on insulin resistance and lipid metabolism

Peroxisome proliferator-activated receptors (PPARs) α and γ are key regulators of lipid homeostasis and insulin resistance. In this study␣we show that a novel compound, 3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}- 2-[2-(2-nitro-phenoxy)-acetyl amino]-propionic acid (O325H), is an agonist with dual effect on PPARα/γ by using dual-luciferase reporter gene assay. By activating PPARα and PPARγ simultaneously, O325H promotes pre-adipocyte differentiation and up-regulates the expression of glucose and lipid metabolic target genes. In diabetic mice, administration of O325H at 10 mg/kg decreases the blood lipid and glucose levels. Therefore, O325H has dual action on PPARα and PPARγ and is a promising agent for the amelioration of lipid metabolic disorders and diabetes associated with insulin resistance.     

Suppression of intestinal inflammation and inflammation-driven colon cancer in mice by dietary sphingomyelin: importance of peroxisome proliferator-activated receptor γ expression

Inflammation of the gastrointestinal tract increases the risk of developing colon cancer especially in younger adults. Dietary compounds are not only associated with the etiology of inflammation and colon cancer but also in their prevention. Sphingolipid metabolites have been shown to play a role in the initiation and perpetuation of inflammatory responses. In the present study, we investigated the suppression of dextran sodium sulfate-induced colitis and azoxymethane-induced colon cancer by dietary sphingomyelin (SM) in mice that lack functional peroxisome proliferator-activated receptor γ (PPAR-γ) in intestinal epithelial and immune cells. Dietary SM decreased disease activity and colonic inflammatory lesions in mice of both genotypes but more efficiently in mice expressing PPAR-γ. The increased survival and suppression of tumor formation in the SM-fed mice appeared to be independent of PPAR-γ expression in immune and epithelial cells. Using a real-time polymerase chain reaction array, we detected an up-regulation in genes involved in Th1 (interferon γ) and Th17 (interleukin [IL]-17 and IL-23) responses despite the reduced inflammation scores. However, the genes involved in Th2 (IL-4, IL-13 and IL-13ra2) and Treg (IL-10rb) anti-inflammatory responses were up-regulated in a PPAR-γ-dependent manner. In line with the PPAR-γ dependency of our in vivo findings, treatment of RAW macrophages with sphingosine increased the PPAR-γ reporter activity. In conclusion, dietary SM modulated inflammatory responses at the early stages of the disease by activating PPAR-γ, but its anticarcinogenic effects followed a PPAR-γ-independent pattern.     

Cystathionine γ lyase–hydrogen sulfide increases peroxisome proliferator-activated receptor γ activity by sulfhydration at C139 site thereby promoting glucose uptake and lipid storage in adipocytes

Adipocytes express the cystathionine γ lyase (CSE)–hydrogen sulfide (H₂S) system. CSE–H₂S promotes adipogenesis but ameliorates adipocyte insulin resistance. We investigated the mechanism of how CSE–H₂S induces these paradoxical effects. First, we confirmed that an H₂S donor or CSE overexpression promoted adipocyte differentiation. Second, we found that H₂S donor inhibited but CSE inhibition increased phosphodiesterase (PDE) activity. H₂S replacing isobutylmethylxanthine in the differentiation program induced adipocyte differentiation in part. Inhibiting PDE activity by H₂S induced peroxisome proliferator activated receptor γ (PPARγ) protein and mRNA expression. Of note, H₂S directly sulfhydrated PPARγ protein. Sulfhydrated PPARγ increased its nuclear accumulation, DNA binding activity and adipogenesis gene expression, thereby increasing glucose uptake and lipid storage, which were blocked by the desulfhydration reagent DTT. H₂S induced PPARγ sulfhydration, which was blocked by mutation of the C139 site of PPARγ. In mice fed a high-fat diet (HFD) for 4 weeks, the CSE inhibitor decreased but H₂S donor increased adipocyte numbers. In obese mice fed an HFD for 13 weeks, H₂S treatment increased PPARγ sulfhydration in adipose tissues and attenuated insulin resistance but did not increase obesity. In conclusion, CSE–H₂S increased PPARγ activity by direct sulfhydration at the C139 site, thereby changing glucose into triglyceride storage in adipocytes. CSE–H₂S-mediated PPARγ activation might be a new therapeutic target for diabetes associated with obesity.     

Meldonium improves Huntington’s disease mitochondrial dysfunction by restoring peroxisome proliferator-activated receptor γ coactivator 1α expression

Mitochondrial dysfunction seems to play a fundamental role in the pathogenesis of neurodegeneration in Huntington’s disease (HD). We assessed possible neuroprotective actions of meldonium, a small molecule affecting mitochondrial fuel metabolism, in in vitro and in vivo HD models. We found that meldonium was able to prevent cytotoxicity induced by serum deprivation, to reduce the accumulation of mutated huntingtin (mHtt) aggregates, and to upregulate the expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in mHTT-expressing cells. The PGC-1α increase was accompanied by the increment of mitochondrial mass and by the rebalancing of mitochondrial dynamics with a promotion of the mitochondrial fusion. Meldonium-induced PGC-1α significantly alleviated motor dysfunction and prolonged the survival of a transgenic HD Drosophila model in which mHtt expression in the nervous system led to progressive motor performance deficits. Our study strongly suggests that PGC-1α, as a master coregulator of mitochondrial biogenesis, energy homeostasis, and antioxidant defense, is a potential therapeutic target in HD.