PPAR

Colorectal cancer (CRC) is the second most fatal and the third most diagnosed type of cancer worldwide. Despite having multifactorial causes, most CRC cases are mainly determined by dietary factors. In recent years, a large number of studies have attributed a protective effect to polyphenols and foods containing these compounds (fruits and vegetables) against CRC. Indeed, polyphenols have been reported

The nuclear receptor peroxisome proliferator – activated receptor
(PPAR)a is known primarily as a regulator of fatty acid metab-
olism, energy balance, and inflammation, but evidence suggests
a wider role in regulating the biotransformation of drugs and
other lipophilic chemicals. We investigated whether PPARa
directly regulates the transcription of cytochrome P450 3A4, the
major human drug-metabolizing enzyme. Using chromatin im-
munoprecipitation in human primary hepatocytes as well as
electrophoretic mobility shift and luciferase reporter-gene as-
says, we identified three functional PPARa-binding regions
(PBR-I, -II, and -III) within ∼ 12 kb of the CYP3A4 upstream
sequence. Furthermore, a humanized CYP3A4/3A7 mouse model
showed in vivo induction of CYP3A4 mRNA and protein by [4-
chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (WY14,643)
in liver but not in intestine, whereas hepatic occupancy of
PBRs by PPARa was ligand independent. Using lentiviral gene
knock-down and treatment with WY14,643 in primary human
hepatocytes, PPARa was further shown to affect the expres-
sion of a distinct set of CYPs, including 1A1, 1A2, 2B6, 2C8,
3A4, and 7A1, but not 2C9, 2C19, 2D6, or 2E1. Interestingly,
the common phospholipid 1-palmitoyl-2-oleoyl-sn-glycerol-3-
phosphocholine (16:0/18:1-PC), previously proposed to reflect
nutritional status and shown to be a specific endogenous
ligand of PPARa, induced CYP3A4 (up to 4-fold) and other
biotransformation genes in hepatocytes with similar selectivity
and potency as WY14,643. These data establish PPARa as a
direct transcriptional regulator of hepatic CYP3A4. This finding
warrants investigation of both known and newly developed
PPARa-targeted drugs for their drug-drug interaction potential.
Furthermore, our data suggest that nutritional status can influ-
ence drug biotransformation capacity via endogenous phos-
pholipid signaling.

Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are important for preventing adverse cardiovascular events not only in patients with a high risk of vascular disease but also in those with a low risk, by reducing the levels of low-density lipoprotein cholesterol. Statin is associated with deteriorating glucose homeostasis and an increased risk of diabetes mellitus. Moreover, these off-target effects are dose-dependent; it has also been suggested that renal insult can be caused dose-dependently by statin treatment, in contrast to previous studies showing a renoprotective effect. The 2013 American College of Cardiology/American Heart Association guidelines recommend the use of high-intensity statin therapy, and extend its use to more people at risk of vascular diseases. However, a European committee has expressed concerns about the potential side effects of using statins in a large fraction of the population for extended periods. This is true of Asian people, for w...

The sirtuin family comprises seven NAD+-dependent deacetylases which control the overall health of organisms through the regulation of pleiotropic metabolic pathways. Sirtuins are important modulators of adipose tissue metabolism and their expression is higher in lean than obese subjects. At present, the role of sirtuins in adipose-derived stem cells has not been investigated yet. Therefore, in this study, we evaluated the expression of the complete panel of sirtuins in adipose-derived stem cells isolated from both subcutaneous and visceral fat of non-obese and obese subjects. We aimed at investigating the influence of obesity on sirtuins’ levels, their role in obesity-associated inflammation, and the relationship with the peroxisome proliferator-activated receptor delta, which also plays functions in adipose tissue metabolism. The mRNA levels in the four types of adipose-derived stem cells were evaluated by quantitative polymerase chain reaction, in untreated cells and also after 8 h of hypoxia exposure. Correlations among sirtuins’ expression and clinical and molecular parameters were also analyzed. We found that sirtuin1–6 exhibited significant higher mRNA expression in visceral adipose-derived stem cells compared to subcutaneous adipose-derived stem cells of non-obese subjects. Sirtuin1–6 levels were markedly reduced in visceral adipose-derived stem cells of obese patients. Sirtuins’ expression in visceral adipose-derived stem cells correlated negatively with body mass index and C-reactive protein and positively with peroxisome proliferator-activated receptor delta. Finally, only in the visceral adipose-derived stem cells of obese patients hypoxia-induced mRNA expression of all of the sirtuins. Our results highlight that sirtuins’ levels in adipose-derived stem cells are consistent with protective effects against visceral obesity and inflammation, and suggest a transcriptional mechanism through which acute hypoxia up-regulates sirtuins in the visceral adipose-derived stem cells of obese patients.

Chronic kidney disease (CKD) is well known as a strong risk factor for both end stage renal disease and cardiovascular disease. To clarify the association of polymorphisms in thePPARgenes (PPARD,PPARG, andPPARGC1A) with the risk of CKD in Japanese, we examined this association among the Japanese subjects using the cross-sectional data of J-MICC (Japan Multi-Institutional Collaborative Cohort) Study. The subjects for this analysis were 3,285 men and women, aged 35–69 years, selected from J-MICC Study participants; genotyping was conducted by multiplex polymerase chain reaction-based Invader assay. The prevalence of CKD was determined for CKD stages 3–5 (defined as eGFR < 60 ml/min/1.73 m2). Participants with CKD accounted for 17.3% of the study population. When those withPPARDT-842CT/Twere defined as reference, those withPPARDT-842CT/CandC/Cdemonstrated the OR for CKD of 1.26 (95%CI 1.04–1.53) and 1.31 (95%CI 0.83–2.06), respectively. There were no significant associations between...

Metabolic related diseases, such as type 2 diabetes, metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD), are widespread threats which bring about a significant burden of deaths worldwide, mainly due to cardiovascular events and cancer. The pathogenesis of these diseases is extremely complex, multifactorial, and only partially understood. As the main metabolic organ, the liver is central to maintain whole body energetic homeostasis. At the cellular level, mitochondria are the metabolic hub connecting and integrating all the main biochemical, hormonal, and inflammatory signaling pathways to fulfill the energetic and biosynthetic demand of the cell. In the liver, mitochondria metabolism needs to cope with the energetic regulation of the whole body. The nuclear receptors PPARs orchestrate lipid and glucose metabolism and are involved in a variety of diseases, from metabolic disorders to cancer. In this review, focus is placed on the roles of PPARs in the regulation of live...

Both peroxisome activator proteins (PPARs) and fetuin-A play a role in lipid and glucose metabolism. We investigated whether PPARα intron 7 G2468/C and PPARγ2 Pro12Ala and PPARγ exon 6 C161T polymorphisms are associated with serum fetuin-A concentrations. The PPARα intron 7 G/C polymorphism was studied in cohort 1 (79 reference individuals, 165 postinfarction patients). The two PPARγ polymorphisms were investigated in cohort 2 (162 reference individuals, 165 postinfarction patients). Fetuin-A levels and PPAR polymorphisms were determined by radial immunodiffusion and polymerase chain reaction-restriction fragment length polymorphism techniques. The C allele variant of PPARα intron 7 G2467C was associated with higher fetuin-A levels (p = 0.018). Postinfarction status (p = 0.001), PPARα intron 7 GG/GC/CC genotypes (p = 0.032), and the C allele (p = 0.021) were the strongest determinants of fetuin-A concentration in a multiple regression model. Higher fetuin-A levels were associated wi...

The expression and signaling of the vitamin D receptor (VDR) and peroxisome proliferator-activated receptor (PPAR) alpha, delta, gamma was investigated in the melanoma cell line MeWo. Using real-time PCR, the mRNA of the nuclear receptors (NR) was detected. The strongest expression was found for the VDR, approximately 3-fold higher compared to the expression of PPARalpha or PPARdelta, and the weakest expression was for PPARgamma. After treatment with corresponding ligands, the expression of the VDR, PPARalpha and PPARdelta was elevated up to 5-fold, while the PPARgamma expression was not significantly affected. Treatment with 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3, calcitrol) resulted in 40% inhibition of MeWo cell proliferation, that was associated with a 5-fold increase in VDR mRNA. Interestingly, cell proliferation was differentially modulated by treatment with the PPAR ligands. While docosahexaenoic acid (DHA) treatment resulted in a statistically significant increase (appro...