17ß-estradiol improves hepatic mitochondrial biogenesis and function through PGC1B.

Sexual dimorphism in mitochondrial biogenesis and function has been described in many rat tissues, with females showing larger and more functional mitochondria. The family of the peroxisome proliferator-activated receptor gamma coactivator 1 (PGC1) plays a central role in the regulatory network governing mitochondrial biogenesis and function, but little is known about the different contribution of hepatic PGC1A and PGC1B in these processes. The aim of this study was to elucidate the role of 17ß-estradiol (E2) in mitochondrial biogenesis and function in liver and assess the contribution of both hepatic PGC1A and PGC1B as mediators of these effects. In ovariectomized (OVX) rats (half of which were treated with E2) estrogen deficiency led to impaired mitochondrial biogenesis and function, increased oxidative stress, and defective lipid metabolism, but was counteracted by E2 treatment. In HepG2 hepatocytes, the role of E2 in enhancing mitochondrial biogenesis and function was confirmed. These effects were unaffected by the knockdown of PGC1A, but were impaired when PGC1B expression was knocked down by specific siRNA. Our results reveal a widespread protective role of E2 in hepatocytes, which is explained by enhanced mitochondrial content and oxidative capacity, lower hepatic lipid accumulation, and a reduction of oxidative stress. We also suggest a novel hepatic protective role of PGC1B as a modulator of E2 effects on mitochondrial biogenesis and function supporting activation of PGC1B as a therapeutic target for hepatic mitochondrial disorders.

Sex-dependent differences in rat hepatic lipid accumulation and insulin sensitivity in response to diet-induced obesity.

Ectopic deposition of lipids in liver and other extrahepatic tissues alters their function and occurs once adipose tissue fat storage capacity is exceeded. We investigated sexual dimorphism in the effects of dietary obesity on the liver insulin signaling pathway, as well as its connection to differences in hepatic fat accumulation. Ten-week-old Wistar rats of both sexes were fed a standard diet or a high-fat diet for 26 weeks. Insulin, adipokine levels, and glucose tolerance were measured. Lipid content, PPARα mRNA expression and protein levels of insulin receptor subunit ß (IRß), IR substrate 2 (IRS-2), Ser/Thr kinase A (Akt), and pyruvate dehydrogenase kinase isozyme 4 (PDK4) were measured in liver. In control rats, serum parameters and hepatic levels of IRß, IRS-2, and Akt proteins pointed to a profile of better insulin sensitivity in females. In response to dietary treatment, female rats exhibited a greater increase in body mass and adiposity and lower liver fat accumulation than males, but maintained better glucose tolerance. The reduced insulin signaling capacity in the liver of obese female rats seems to prevent lipid accumulation and probably lipotoxicity-associated hepatic disorders.

Phytotherapy in a rat model of hyperoxaluria: the antioxidant effects of quercetin involve serum paraoxonase 1 activation.

Serum paraoxonase 1 (PON1) has been reported to be an important contributor to the antioxidant and anti-inflammatory activities of HDL, avoiding LDL oxidation. The activity of this enzyme is reduced in patients with renal insufficiency, caused by elevated oxidative stress and disturbances of apolipoprotein metabolism. Therapeutic utilization of antioxidants to control renal oxidative stress may be an effective therapy in renal protection. The aim was to investigate the protective effects of several antioxidant compounds against the oxidative stress associated to renal failure induced by ethylene glycol (EG), focusing on the possible role of serum PON1 activity. Fifty-four male Wistar rats were randomly assigned to six groups (n = 9): an untreated control (C) group, an EG-treated group, a catechin (CAT)-treated group, an epicatechin (EPI)-treated group, a quercetin (QUE)-treated group and a folk herbal extract (FHE)-treated group. After 16 d of treatment, calcium oxalate lithiasis was induced in the rats using EG. After eight days (treatment + EG), the animals were sacrificed. EG treatment impaired kidney composition, increased oxidative damage, and decreased serum paraoxonase and arylesterase activities. CAT, QUE and the FHE Fagolitos improved oxidative status by enhancing antioxidant defenses - superoxide dismutase and PON1 activities - and reducing oxidative damage, thus reinforcing the idea of a possible role of PON1 in the protective effects of QUE against the deleterious consequences of oxidative stress in kidney.

Effects of ovariectomy and 17-ß estradiol replacement on rat brown adipose tissue mitochondrial function.

Taking into account the sexual dimorphism previously reported regarding mitochondrial function and biogenesis in brown adipose tissue, the aim of the present study was to go further into these differences by investigating the effect of ovariectomy and 17-ß estradiol (E2) replacement on brown adipose tissue mitochondrial function. In this study, fourteen-week-old control female and ovariectomized female Wistar rats were used. Rats were ovariectomized at 5 weeks of age and were treated every 2 days with placebo (OVX group) or E2 (10 µg/kg) (OVX+E2 group) for 4 weeks before sacrifice. We studied the levels of oxidative capacity, antioxidant defence and oxidative damage markers in brown adipose tissue. Moreover, the levels of key elements of mitochondrial biogenesis as well as UCP1 protein levels, as an index of mitochondrial thermogenic capacity, were also determined. In response to ovariectomy, mitochondrial proliferation increased, resulting in less functional mitochondria, since oxidative capacity and antioxidant defences decreased. Although E2 supplementation was able to restore the serum levels of E2 shown by control rats, the treatment reverted the effects of the ovariectomy only in part, and oxidative and antioxidant capacities in OVX+E2 rats did not reach the levels shown by control females. Taking these results into account, we suggest that ovarian hormones are responsible, at least in part, for the sexual dimorphism in BAT mitochondrial function. However, other signals produced by ovary, rather than E2, would play an important role in the control of mitochondrial function in BAT.

Long-term high-fat-diet feeding impairs mitochondrial biogenesis in liver of male and female rats.

BACKGROUND/AIMS: Mitochondrial biogenesis includes both mitochondrial proliferation and differentiation and its regulation under different physiological conditions is not clear. Given the sexual dimorphism previously found in mitochondrial function, the aim of this study was to investigate the gender-dependent effect of chronic high-fat-diet (HFD) feeding on rat liver mitochondrial function and biogenesis. METHODS: Ten-week old male and female rats were fed a HFD (26% fat) or a control diet (2.9% fat) for 26 weeks. Mitochondrial morphology was studied. Mitochondrial DNA and protein content, hydrogen peroxide production, oxidative capacity, antioxidant defenses, as well as markers of oxidative damage and mitochondrial biogenesis were analyzed. RESULTS: Female rats showed higher levels of mitochondrial protein and an enhanced oxidative capacity per mitochondrion than males. In both genders, HFD feeding increased mtDNA content and decreased mitochondrial differentiation markers. CONCLUSION: In comparison to male rats, females show higher oxidative capacity as a consequence of their greater mitochondrial differentiation under both control and obese status. In response to HFD feeding, the oxidative capacity of the whole mitochondrial population is maintained in both genders. This is obtained by means of an enhancement of mitochondrial proliferation, which counteracts the diet-induced impairment of the function of each mitochondrion.

Time-dependent modulation of rat serum paraoxonase 1 activity by fasting.

High-density lipoprotein-associated paraoxonase 1 (PON1) protects the endothelium from the pro-oxidant activity of oxidised low-density lipoprotein. Whereas fasting has been related to increased oxidative stress, intermittent fasting and caloric restriction are associated to increased resistance to oxidative injury. Taking into consideration that serum PON1 activity is modulated by a restriction of caloric intake and because there is no evidence regarding PON1 response to total food deprivation, we investigated whether PON1 activity is involved in the response aimed to counteract the greater oxidative stress associated to fasting and whether serum PON1 activity is altered by the length of food deprivation. Male Wistar rats were randomly divided into five groups: fed and 6-, 12-, 24- or 48-h fasted rats. Serum PON1 activity increases within the first hours of fasting, representing a prompt adaptation designed to attenuate blood lipid peroxidation that cannot be sustained when fasting is prolonged. This PON1 response to early fasting could be part of the mechanisms triggered by periodically repeated short periods of food deprivation - intermittent fasting - which result in increased resistance to stress by stimulating antioxidant defences.