How Does Testosterone Raise Lipids

How Does Testosterone Raise Lipids

• Research
• Open Access
• Published: 07 March 2015

Effect of testosterone deficiency on cholesterol metabolism in pigs fed a high-fat and high-cholesterol diet

• Haitao Xi²,
• Yongming Pan¹,
• Xiaoling Jiang³,
• Liang Chen¹,
• Yueqin Cai¹,
• Keyan Zhu¹,
• Cheng Chen¹,
• Xiaoping Xu¹ &
• Minli Chen¹

Lipids in Health and Disease volume 14, Article number:18 (2015) Cite this article

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Abstract

Background

Testosterone deficiency is associated with increased serum cholesterol levels. However, how testosterone deficiency precisely affects cholesterol metabolism remains unclear. Therefore, in the current study, we examined the effect of testosterone deficiency on cholesterol metabolism and liver gene expression in pigs fed a high-fat and high-cholesterol (HFC) diet.

Methods

Sexually mature male miniature pigs (6–7 months old) were randomly divided into 3 groups as follows: intact male pigs fed an HFC diet (IM + HFC), castrated male pigs fed an HFC diet (CM + HFC), and castrated pigs with testosterone replacement fed an HFC diet (CM + HFC + T). Serum testosterone levels and lipid profiles were measured, and gene expression levels associated with hepatic cholesterol metabolism were determined. Furthermore, total hepatic cholesterol contents and the activities of enzymes mediating hepatic cholesterol metabolism were measured.

Results

Serum testosterone levels were significantly decreased in CM + HFC pigs, and testosterone replacement attenuated castration-induced testosterone deficiency. Castration significantly increased the serum levels of total cholesterol, low-density lipoprotein cholesterol and triglycerides, as well as hepatic lipid contents in pigs fed an HFC diet. Compared with IM + HFC and CM + HFC + T pigs, low-density lipoprotein receptor (LDLR) mRNA expression and protein levels were significantly decreased in the livers of CM + HFC pigs. In contrast, we found that compared with IM + HFC pigs, hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA and serum PCSK9 protein levels were significantly increased in CM + HFC pigs. Moreover, testosterone treatment reversed the increase in PCSK9 expression in CM + HFC pigs. However, neither castration nor testosterone replacement affected the expression of the other hepatic genes that were tested.

Conclusions

This study demonstrated that castration-induced testosterone deficiency caused severe hypercholesterolemia in pigs fed an HFC diet; furthermore, these effects could be reversed by testosterone replacement therapy. Altered hepatic PCSK9 and LDLR expression, resulting in reduced LDL-cholesterol clearance, may contribute to the increased serum cholesterol levels induced by testosterone deficiency and an HFC diet. These results deepen our understanding of the underlying molecular mechanisms that mediate the effects of testosterone deficiency on cholesterol metabolism.

Background

Aging in men causes a gradual decline in endogenous testosterone levels [1], which may have detrimental effects on health status [2]. Numerous studies have shown that low levels of endogenous testosterone are associated with an increased risk of atherosclerosis in men [3]-[5], and serum lipids are essential for atherosclerosis development [6],[7]. Testosterone deficiency is thought to promote atherosclerosis by modulating lipid metabolism [8]. Several clinical and epidemiological studies have reported that serum testosterone levels are inversely correlated with total cholesterol and LDL cholesterol levels [9]-[11]. Moreover, animal studies have also demonstrated markedly increased serum cholesterol levels in testosterone-deficient male mice [12],[13]. These findings indicate that testosterone serves an important role in regulating serum cholesterol metabolism. However, to date the potential molecular mechanisms whereby testosterone deficiency affects cholesterol metabolism are unclear.

The liver is a critical organ for normal cholesterol metabolism and contains numerous proteins and enzymes related to cholesterol homoeostasis. Three well-studied examples of such enzymes include 3-hydroxy-3-methylgutaryl coenzyme A reductase (HMGCR), which is the rate-limiting enzyme in cholesterol synthesis; the low-density lipoprotein receptor (LDLR), which is responsible for the removal of LDL-cholesterol from the blood; and cholesterol 7α-hydroxylase (CYP7A1), which is the main enzyme responsible for catalyzing the conversion of cholesterol into bile acids and reverse cholesterol transport [14]. Furthermore, sterol regulatory element-binding protein 2 (SREBP2) governs transcriptional activation of LDLR and HMGCR, whereas liver X receptor alpha (LXRα) regulates the transcription of CYP7A1[15]. To date, limited data are available regarding the effects of testosterone on the modulation of hepatic cholesterol homeostasis-related proteins. Therefore, it is unknown whether a testosterone deficiency-induced increase in serum cholesterol levels is related to changes in hepatic protein expression that are involved in cholesterol metabolism.

Here, we aimed to determine the effect of testosterone deficiency on cholesterol metabolism in pigs fed an HFC diet. In additional, we explored potential associated mechanisms by measuring the expression of genes related to hepatic cholesterol metabolism.

Methods

Animals and experimental procedures

All experimental procedures used in this study were approved by the Institutional Animal Care and Use Committee of the Zhejiang Chinese Medical University (Hangzhou, China). Eighteen sexually mature male Chinese Wuzhishan (WZS) miniature pigs (6–7 months old) were obtained from the Institute of Animal Sciences, Hainan Academy of Agricultural Sciences (Haikou, China). The animals were housed in individual pens under environmental conditions with a room temperature of 22°C ± 3°C, a relative humidity of 50% ± 20% and a 12-hour light/dark cycle. The study protocol is outlined in Figure 1. The animals received a standard diet without cholesterol during a 7-week "pretreatment period" to facilitate acclimation to the environment and baseline determinations. At week 7, the pigs were either surgically castrated or given a sham operation, as described previously [16]. Testosterone was administrated weekly to castrated pigs via intramuscular injection with testosterone propionate (10 mg/kg body weight; Sigma-Aldrich, St. Louis, MO, USA) dissolved in corn oil [17]. Testosterone replacement therapy was given on the same day of castration to avoid the disruption of hormonal influences. Pigs were fed an HFC diet starting from week 8 and were divided into 3 groups (n = 6 animals/group) as follows: intact male pigs fed an HFC diet (IM + HFC), castrated male pigs fed an HFC diet (CM + HFC), and castrated pigs with testosterone replacement fed an HFC diet (CM + HFC + T). The HFC diet used in this study was comprised of 73% normal swine diet, 15% lard, 10% egg yolk power, 1.5% cholesterol, and 0.5% sodium cholate. The HFC diet was similar to an atherogenic diet, which has been shown to induce hypercholesterolemia and atherosclerosis in pigs [18],[19]. Body weights were recorded weekly, and the study period was 12 weeks.

Figure 1

Schematic representation of the experimental design. Sexually mature male miniature pigs (6–7 months old) were fed a standard diet without cholesterol for 7 weeks. At week 7, the pigs were either surgically castrated or given a sham operation. Moreover, testosterone replacement therapy was given on the day of castration. Beginning at week 8, intact male pigs (IM + HFC), castrated pigs (CM + HFC), and castrated male pigs with testosterone replacement (CM + HFC + T) were fed the same high-fat and high cholesterol (HFC) diet for another 12 weeks, after which they were euthanized.

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At the end of the experimental period, the animals were sacrificed by exsanguination under anesthesia. The carcasses were eviscerated as previously described [20], livers were removed and weighed, and liver weight indexes were calculated as liver weight/body weight ratios. Livers were then frozen immediately in liquid nitrogen and stored at −80°C for further analysis.

Analysis of serum parameters

Fasting blood samples were collected prior to castration and twice weekly throughout the study. Sera were separated from collected blood samples by centrifugation at 3000 ×g at 4°C for 15 min and stored at −80°C for further analysis. Serum testosterone concentrations were measured at week 7 (0 w; the start of the experimental period after the 7-week acclimation) and week 19 (12 w; the end of the experimental period), using a commercial radioimmunoassay kit (North Institute of Biological Technology, Beijing, China).

Serum samples were analyzed to determine serum lipid levels. Total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and total triglyceride (TG) were measured with commercial kits (Rongsheng Biotech, Co., Ltd., Shanghai, China) using an Automatic Biochemistry Analyzer (Hitachi 7020, Tokyo, Japan). Serum PCSK9 was measured using a commercial enzyme-linked immunoassay (ELISA) kit (HaiTai TongDa Sci Tech, Co., Ltd., Beijing, China) according to the manufacturer's instructions.

Biochemical analysis in liver tissues

Liver samples were studied to determine the hepatic TC and TG contents and enzyme activities. Hepatic lipids were measured as described by Shi et al. [21] with slight modifications. Briefly, liver samples from each pig were homogenized at 4°C in phosphate-buffered saline (pH 7.2). Liver samples were then centrifuged at 3000 ×g for 10 min at 4°C, and TC and TG levels in the resulting supernatants were determined using commercially available kits (Rongsheng Biotech, Co., Ltd., Shanghai, China), according to the manufacturer's instructions. Protein concentrations in liver samples were measured with a BCA Assay Kit (Pierce, Rockford, IL, USA).

Enzymatic HMGCR and CYP7A1 activities, as well as LDLR concentrations, present in the livers were measured using commercial ELISA kits (Biovol Biotech, Co., Ltd., Shanghai, China), as described previously [21].

Quantitative real-time PCR analyses

Total RNA from liver specimens was isolated using TRIzol reagent (Invitrogen, Carlsbad, CA, USA) according to the manufacturer's instructions. One microgram of total RNA was reverse transcribed into cDNA using an MMLV-RT Kit (Promega, Madison, WI, USA) according to the manufacturer's protocol. Real-time PCR was performed using the StepOnePlus Real-Time PCR Detection System (Applied Biosystems, Inc., Foster City, CA, USA). The sequences of primers used for measuring mRNA expression levels are shown in Table 1. Amplifications were performed in 20-μL reaction mixtures containing 10.4 μL of 2× SYBR Premix Ex Taq (TaKaRa, Dalian, China), 0.4 μL of each primer (10 mM), 7.8 μL of distilled water, and 1.0 μL of cDNA. The following thermocycling conditions were used for all real-time PCR reactions: 95°C for 5 min, followed by 40 cycles of 95°C for 15 s, 60°C for 30 s, and 72°C for 30 s. After amplification, melt curve analysis was performed to confirm the reaction specificities. All measurements were performed in triplicate. β-Actin was used as a reference gene to normalize gene expression. The 2^-∆∆CT method was used to analyze the qRT-PCR data and assign relative expression differences [22].

Table 1 Primers used for quantitative real-time RT-PCR

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Statistical analysis

The results are presented as mean ± SEM. The data were analyzed by one-way analysis of variance (ANOVA), followed by Tukey's test. Correlation analysis was performed using Pearson's test. P values of less than 0.05 were considered statistically significant. All statistical analyses were performed by using SPSS software, version 13.0 (SPSS, Chicago, IL, USA).

Results

Body weight, liver weight, and serum testosterone levels

Body weight, liver weight, and serum testosterone levels in pigs after 12 weeks of being fed an HFC diet are shown in Table 2. Initial body weights were similar in pigs in the IM + HFC, CM + HFC, and CM + HFC + T groups. CM + HFC pigs fed an HFC diet gained less weight than did pigs in the other groups. With testosterone replacement, the body weights of CM + HFC + T pigs increased and were similar to the body weights of pigs in the IM + HFC group (Table 2). Liver weight indexes in CM + HFC pigs were higher than those in the IM + HFC and CM + HFC + T groups, but these differences were not significant (P > 0.05).

Table 2 Body weight, liver weight, and serum testosterone levels in pigs fed a high-fat and high-cholesterol diet ^a

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Serum testosterone levels were not significantly different between groups before the study began. As expected, castration caused a significant decrease in serum testosterone levels. The concentration of serum testosterone at the end of the study was significantly lower in CM + HFC pigs than in IM + HFC pigs (P < 0.01). Testosterone treatment increased serum testosterone levels in CM + HFC + T pigs (P < 0.01; Table 2).

Serum lipid profiles

To analyze the effects of castration and testosterone treatment on serum lipid profiles in HFC-fed pigs, serum lipids were measured at 0, 4, 8, and 12 weeks post castration (Figure 2). CM + HFC pigs had higher TC levels than did IM + HFC and CM + HFC + T pigs by the fourth week of HFC supplementation (P < 0.01; Figure 2A). There were no significant differences in serum TC levels between IM + HFC and CM + HFC + T pigs (P > 0.05). Serum LDL-C followed a pattern similar to that of TC in all groups of pigs (Figure 2B). However, testosterone deficiency caused by castration had no significant influence on serum HDL-C levels in HFC-fed pigs (Figure 2C). Serum TG levels in CM + HFC pigs were higher than those in IM + HFC pigs at week 12 (P < 0.01) and those in CM + HFC + T pigs at weeks 4, 8, and 12 (P < 0.05; Figure 2D).

Figure 2

Effects of castration and testosterone replacement on serum total cholesterol (A), LDL-cholesterol (B), HDL-cholesterol (C), and triglyceride (D) levels in pigs fed a high-fat and high-cholesterol diet. Data are presented as mean ± SEM; n = 6 pigs per group. *P < 0.05 and **P < 0.01, IM + HFC vs. CM + HFC group; ^# P < 0.05 and ^## P < 0.01, CM + HFC + T vs. CM + HFC group. Significant differences were determined by analysis of variance (ANOVA; Tukey's test).

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Hepatic lipid contents

As illustrated in Figure 3, hepatic cholesterol and triglyceride contents were also significantly higher in CM + HFC pigs than in IM + HFC pigs (Figure 3). Moreover, testosterone treatment attenuated the increase in hepatic lipid contents in CM + HFC pigs (Figure 3).

Figure 3

Effects of castration and testosterone replacement on hepatic lipid contents in pigs fed a high-fat and high-cholesterol diet. (A) Hepatic cholesterol contents. (B) Hepatic triglyceride contents. Data are presented as mean ± SEM; n = 6 pigs per group. *P < 0.05, **P < 0.01. Significant differences compared to the CM + HFC group determined by ANOVA (Tukey's test).

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Hepatic mRNA expressions of genes involved in cholesterol metabolism

To investigate the effects of testosterone on the expression of genes controlling hepatic cholesterol metabolism, mRNA expression levels of SREBP2, LXRα, HMGCR, LDLR, CYP7A1, and PCSK9 were studied by quantitative real-time PCR (Figure 4). The results showed that castration and testosterone replacement did not affect hepatic expression of SREBP2, LXRα, HMGCR, or CYP7A1 at the mRNA level (Figure 4). However, castration markedly suppressed hepatic LDLR expression in CM + HFC pigs with respect to IM + HFC pigs and CM + HFC + T pigs (P < 0.05; Figure 4). In contrast, castration-induced testosterone deficiency induced a 4.3-fold increase in hepatic expression of PCSK9 mRNA. Moreover, testosterone treatment restored increased expression of PCSK9 in CM + HFC pigs (P < 0.01; Figure 4).

Figure 4

Effects of castration and testosterone replacement on liver SREBP2 (A), LXRα (B), HMGCR (C), LDLR (D), CYP7A1 (E), and PCSK9 (F) mRNA expression in pigs fed a high-fat and high-cholesterol diet. SREBP2, sterol regulatory element binding protein 2; LXRα, liver X receptor alpha; HMGCR, 3-hydroxy-3-methylgutaryl coenzyme A reductase; LDLR, low-density lipoprotein receptor; CYP7A1, cholesterol 7α-hydroxylase; PCSK9, proprotein convertase subtilisin/kexin type 9. Data are presented as mean ± SEM; n = 6 pigs per group. *P < 0.05, significant differences compared to the CM + HFC group determined by ANOVA (Tukey's test).

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Enzyme activities of HMGCR, LDLR, CYP7A1, and PCSK9

Hepatic HMGCR and CYP7A1 activities, LDLR concentrations, and serum PCSK9 levels were measured, as shown in Figure 5. Evidently, neither castration nor testosterone treatment affected the activities of HMGCR or CYP7A1 in the liver of pigs (P > 0.05) (Figure 5A and 5B). However, testosterone deficiency significantly reduced hepatic LDLR protein levels in CM + HFC pigs (P < 0.01). Moreover, testosterone replacement reversed the reduction in hepatic LDLR levels in CM + HFC pigs (P < 0.05; Figure 5C). Serum PCSK9 levels were significantly increased by castration in pigs (P < 0.05), but this effect was reversed by testosterone replacement (Figure 5D).

Figure 5

Effects of castration and testosterone replacement on hepatic HMGCR (A), CYP7A1 (B) activities, LDLR concentrations (C), and serum PCSK9 levels (D) in pigs fed a high-fat and high-cholesterol diet. HMGCR, 3-hydroxy-3-methylgutaryl coenzyme A reductase; CYP7A1, cholesterol 7α-hydroxylase; PCSK9, proprotein convertase subtilisin/kexin type 9. Data are presented as mean ± SEM; n = 6 pigs per group. *P < 0.05, **P < 0.01. Significant differences compared to the CM + HFC group determined by ANOVA (Tukey's test).

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Correlations between serum PCSK9 levels and LDL-C and TC levels

We next investigated the correlation between serum PCSK9 levels and LDL-C and TC levels in pigs fed an HFC diet. As shown in Figure 6, serum levels of PCSK9 were positively correlated with LDL-C (r = 0.620, P = 0.006) and TC (r = 0.489, P = 0.023).

Figure 6

Correlations between serum levels of PCSK9 and LDL-C or TC. PCSK9, proprotein convertase subtilisin/kexin type 9; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol.

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Discussion

In this study, we investigated the effects of testosterone levels on cholesterol metabolism in pigs fed an HFC diet. Our data indicated that CM + HFC pigs gained less weight than did pigs in the other groups. Testosterone deficiency was associated with a loss of lean muscle mass [20],[23], which constitutes approximately 50% of the body mass in pigs [24]. The reduced weight of CM + HFC pigs may be attributable to the loss of skeletal muscle mass induced by castration. Serum cholesterol (total cholesterol and LDL-cholesterol) levels were significantly higher in CM + HFC pigs than in IM + HFC pigs. However, testosterone replacement attenuated these effects in CM + HFC pigs, suggesting that testosterone may play a protective role in diet-induced hypercholesterolemia. To the best of our knowledge, the present study is the first to demonstrate that testosterone deficiency induced by castration aggravates diet-induced hypercholesterolemia in a porcine model. In previous studies, researchers have used rodent models to evaluate the effects of testosterone on serum cholesterol levels; however, the observed relationships between testosterone and serum cholesterol levels are inconclusive [13],[25],[26]. In addition, the process of lipoprotein metabolism differs greatly between rodents and humans [27]. Pigs may be more relevant to the study of cholesterol metabolism because of their high degree of similarity with humans in terms of lipid metabolism and cardiovascular physiology [27]-[29], making them an attractive alternative to rodents. Importantly, our previous study revealed that castration-induced testosterone deficiency results in elevated serum cholesterol levels in pigs fed a normal diet [20], suggesting that pigs are suitable models for studying the effects of sex hormones on cholesterol metabolism.

In addition to its effects on serum cholesterol levels, testosterone deficiency also caused a significant increase in serum TG levels in CM + HFC pigs. TGs in the liver are packaged into very low-density lipoproteins (VLDLs) and exported to the circulation. Excessive production of TG-rich VLDL (VLDL-TG) contributes to hypertriglyceridemia [30]. Many genes are involved in the assembly and secretion of VLDL-TG, such as the microsomal triglyceride transfer protein (MTP) and apolipoprotein A-V (apoA-V) [31],[32]. Previous studies showed that testosterone regulates hepatic MTP expression in rats and mice [25],[33]. ApoA-V was recently identified as an important modulator of TG metabolism and shown to lower plasma TG levels in both humans and animals [31],[34]. The results of recent studies have shown decreased apoA-V expression in obese subjects. Moreover, the treatment of HepG2 cells with insulin decreased apoA-V expression [34],[35]. Testosterone deficiency is associated with obesity and insulin resistance [36],[37]. Thus, testosterone deficiency may affect serum TG levels by altering the expression of genes involved in lipoprotein assembly and secretion. The role of testosterone in regulating TG levels was not the primary goal of our study; although this topic will be investigated in future studies.

Little is known regarding the molecular mechanisms underlying the effects of testosterone deficiency on cholesterol metabolism. Cholesterol homeostasis is controlled by coordinated changes in the expression of multiple genes involved in cholesterol biosynthesis, uptake, and efflux [21]. It was well known that LXRα plays a critical role in cholesterol metabolism [7] and that LXRα expression increases cholesterol efflux by regulating its target genes. CYP7A1 is one of the most important target genes of LXRα and was identified as the rate-limiting enzyme in bile acid-synthesis for cholesterol elimination [15]. In the present study, we observed that castration had no effect on the liver mRNA expression levels of LXRα or CYP7A1 in pigs. These results suggested that the increased cholesterol levels observed in CM + HFC pigs may not have resulted from enhanced cholesterol efflux through the LXRα-CYP7A1 pathway. HMGCR is the rate-limiting enzyme mediating de novo cholesterol synthesis [38]. Similarly, hepatic HMGCR activity and mRNA expression were not changed by castration and testosterone replacement. Thus, testosterone deficiency might not influence the de novo synthesis of cholesterol in the livers of CM + HFC pigs. It is well known that LDLR is a crucially important modulator of plasma LDL-cholesterol levels in humans and animals. Increased LDLR expression was shown to result in reduced serum LDL-cholesterol levels [21]. We found that LDLR mRNA expression and protein levels were significantly decreased in the livers of CM + HFC pigs, compared to IM + HFC and CM + HFC + T pigs. This agreed with our findings that CM + HFC pigs showed a significant increase in both serum LDL-cholesterol and TC levels. Moreover, these findings suggest that one of the mechanisms through which testosterone deficiency can increase serum cholesterol levels in CM + HFC pigs is by decreasing LDLR expression, thus inhibiting the removal of LDL-cholesterol from the circulation. In animals, hepatic LDLR and HMGCR are transcriptionally regulated by SREBP2[15]. However, in the present study hepatic SREBP2 mRNA expression was not influenced by castration and testosterone replacement, suggesting that other mechanisms may participate in the regulation of LDLR. Previous studies demonstrated that hepatic LDLR mRNA transcription can be suppressed by a high-cholesterol diet [39]-[41]. Moreover, dietary cholesterol has been reported to increase hepatic TG and cholesterol stores, which in turn suppresses hepatic LDLR mRNA levels [42]. Thus, the reduced hepatic LDLR mRNA expression observed in CM + HFC pigs may have resulted from an increase in hepatic lipid stores induced by testosterone deficiency and an HFC diet. Recent studies have demonstrated a central role of PCSK9 in the regulation of cholesterol metabolism by enhancing the degradation of hepatic LDLR, resulting in increased serum LDL-cholesterol concentrations [43],[44]. Moreover, results from previous studies indicated that the hormonal and dietary regulation of hepatic LDLR involves posttranscriptional regulation by PCSK9 [45],[46]. Of note, we observed that PCSK9 mRNA expression in liver was significantly increased in CM + HFC pigs compared to IM + HFC and CM + HFC + T pigs. This observation suggested that reduced hepatic LDLR protein levels following castration in CM + HFC pigs may occur via increased PCSK9 expression. In agreement with our findings, data from a recent study demonstrated a reduction in hepatic LDLR levels and severe hypercholesterolemia in PCSK9-transgenic pigs [29]. Taken together, our findings indicate that testosterone deficiency can increase serum LDL-cholesterol and total cholesterol levels by altering the expression of PCSK9 and LDLR, and might increase the risk of atherosclerosis and cardiovascular disease.

This study has several limitations. Only a small set of pigs were included in the study owing to practical issues associated with obtaining the animals. Moreover, we did not measure hepatic testosterone (T) and 17β-estradiol (E2) concentrations. Although testosterone deficiency can increase serum cholesterol levels in HFC-fed pigs, it should be considered that testosterone may be partially effective after being aromatized to estrogen [25]. The direct effects of testosterone were not examined in this study. In addition, we only examined the expression patterns of several key genes involved in cholesterol metabolism. Studying a select few genes cannot rigorously define the genomic mechanisms through which testosterone deficiency induces increased serum cholesterol levels. High-throughput technologies might be needed to assess castration-induced hepatic transcriptome changes in HFC-fed pigs. These issues should be addressed in future studies.

Conclusions

In conclusion, the present study demonstrated that castration-induced testosterone deficiency caused a significant increase in serum cholesterol levels in pigs fed an HFC diet, and these effects were reversed by testosterone replacement. Importantly, testosterone deficiency could induce PCSK9 expression and reduce LDLR expression in the livers of CM + HFC pigs. The findings suggest that the increased serum cholesterol levels observed in CM + HFC pigs may be attributed in part to impaired LDL-cholesterol clearance. The precise mechanisms regulating the hypercholesterolemic effects of testosterone deficiency await more detailed investigation.

Abbreviations

ANOVA:

Analysis of variance

CM + HFC:

Castrated male pigs fed a high-fat and high-cholesterol diet

CM + HFC + T:

Castrated male pigs with testosterone replacement fed a high-fat and high-cholesterol diet

CYP7A1:

Cholesterol 7α-hydroxylase

HDL-C:

High-density lipoprotein cholesterol

HFC:

High-fat and high-cholesterol

HMGCR:

3-hydroxy-3-methylgutaryl coenzyme A reductase

IM + HFC:

Intact male pigs fed a high-fat and high-cholesterol diet

LDL-C:

Low-density lipoprotein cholesterol

LDLR:

Low-density lipoprotein receptor

LXRα:

Liver X receptor alpha

PCSK9:

Proprotein convertase subtilisin/kexin type 9

SREBP2:

Sterol regulatory element binding protein 2

TC:

Total cholesterol

TG:

Triglyceride

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (No. 31200921), Zhejiang Provincial Natural Science Foundation of China (Nos. LQ12C04003 and LY12C04002), and Zhejiang Provincial Department of Science and Technology (No. 2014C37010).

Author information

Affiliations

1. Laboratory Animal Research Center, Zhejiang Chinese Medical University, Hangzhou, 310053, China

   Zhaowei Cai, Yongming Pan, Liang Chen, Yueqin Cai, Keyan Zhu, Cheng Chen, Xiaoping Xu & Minli Chen

2. Reproduction Medicine Center, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325027, China

   Haitao Xi

3. College of Animal Science, Zhejiang University, Hangzhou, 310025, China

   Xiaoling Jiang

Corresponding author

Correspondence to Minli Chen.

Additional information

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

ZWC and LMC conceived and designed the experiments. YQC and ZWC performed the RNA isolation and qRT-PCR analysis. KYZ performed serum biochemical analysis. YMP, LC, ZWC, KYZ, CC, and XPX carried out the animal experiments and participated in sample collection. HTX participated in the design of the study and performed the statistical analysis. ZWC, XLJ, and LMC wrote the manuscript. All authors read and approved the final manuscript.

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Cai, Z., Xi, H., Pan, Y. et al. Effect of testosterone deficiency on cholesterol metabolism in pigs fed a high-fat and high-cholesterol diet. Lipids Health Dis 14, 18 (2015). https://doi.org/10.1186/s12944-015-0014-5

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• Received: 10 December 2014

• Accepted: 20 February 2015

• Published: 07 March 2015

• DOI : https://doi.org/10.1186/s12944-015-0014-5

Keywords

• Testosterone
• Atherosclerosis
• Hypercholesterolemia
• Miniature pigs
• Gene expression

How Does Testosterone Raise Lipids

Source: https://lipidworld.biomedcentral.com/articles/10.1186/s12944-015-0014-5

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Lifetime Liquid B Complex With Vitamin C

Lifetime Liquid B Complex With Vitamin C

A Guide to Vitamin C Serums

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For 70 years Vitamin C has been one of the biggest weapons in the skin care industry. It's used to make cleansers, moisturizers, lotions, masks, and serums. So what is this powerful vitamin? How can it benefit you? Why should you use serums that contain Vitamin C? We're here to answer all of those burning questions in this complete guide and reveal the many benefits Vitamin C serums offer for your skin.

What Are Vitamin C Serums?

There are many variations of Vitamin C, but the most popular is ascorbic acid, a common ingredient in skincare products. However, all the variations of Vitamin C have anti-inflammatory benefits.

Vitamin C Serums are products that contain a high level of Vitamin C. They're used to treat wrinkles, sagging skin, lighten dark or red spots, prevent breakouts and even your skin tone. Basically, they battle all of those annoying skin issues. There are loads of products out there that claim they'll save your skin, but some can cause damage. Vitamin C is one of the most revered ingredients and conclusive research has shown how effective it can be.

How Are Vitamin C Serums Made?

Well so far we've talked about how incredible Vitamin C is and it sounds like a dream come true doesn't it? It's not all good. In fact, the mighty vitamin is unstable when it's exposed to air and light. Other ingredients need to be used to stabilize it and allow it to deliver amazing results. The serums are combined with ferulic acid and Vitamin E. According to researchers the perfect mixture is 15% Vitamin C with 1% Vitamin E and 0.5% ferulic acid. This makes Vitamin C perform to the best of its abilities, without damaging your skin.

What Does Vitamin C Serum Do for Your Face?

Boosts Collagen Production: Collagen keeps your skin firm and prevents sagging. Environmental factors such as lifestyle choices and pollution can increase the elasticity of your skin, so it's important you try to increase your collagen production.

Hydrates Your Skin: Dry skin is a common issue, but Vitamin C can help to give your skin that much-needed moisture boost. Remember, it doesn't work immediately so you need to keep applying the serum to see results.

Brightens Your Complexion: Dark spots on your skin are caused by the overproduction of melanin. Vitamin C decreases the production and lightens the dark spots to even out your complexion.

Reduces Redness and Inflammation: Conditions such as Rosacea leave many people searching for a magic cure. Vitamin C helps facial redness and inflammation by reducing the appearance of broken capillaries.

Why Should You Be Using Vitamin C Serum?

Don't think Vitamin C serums are just beneficial for your face. They can also shield you from sun damage and reduce stretch marks.

Saves You From The Sun: Prolonged exposure to UV rays can cause long-term damage to your skin. Luckily, Vitamin C is a powerful antioxidant that reduces red sports and prevents sunburn from spreading.

Fades Acne Scars: Acne plagues most of us at some point and we look forward to being free. Most of us get stuck with some scars but Vitamin C helps to fade scars and even out any discoloration.

Reduces Stretch Marks: Yes, Vitamin C serum can even help prevent those unsightly stretch marks by tightening your skin.

Are you ready to change your skin? Add a Vitamin C serum to your beauty regimen and enjoy a glowing complexion.

Lifetime Liquid B Complex With Vitamin C

Source: https://www.bloglines.com/article/a-guide-to-vitamin-c-serums?utm_content=params%3Ao%3D740010%26ad%3DdirN%26qo%3DserpIndex

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Is Vitamin C Vegan

Is Vitamin C Vegan

Photo Courtesy: Dean Mitchell/E+/Getty Images

Vitamin A should be an integral part of every person's diet. It plays vital roles in your body by helping to maintain your vision, skin health and even your immune system's ability to work properly. But it's important to consume the right amount; vitamin A can be harmful when your body gets too much of it. Learn more about vitamin A, including what it does, where to find it and what happens when you get too much of it.

Vitamin A is actually a group of fat-soluble vitamins like retinol, retinal and retinyl esters, all of which have various health benefits. Vitamin A is particularly important in the maintenance of vision — especially your ability to see in low light. Your body converts this vitamin to retinal, which combines with other molecules to form rhodopsin. This is the protein principally responsible for your eyes' absorption of light. If you're worried about your vision getting worse over time, make sure you get enough vitamin A. It's a good way to strengthen your sight naturally.

Photo Courtesy: Nastasic/E+/Getty Images

Consuming sufficient amounts of vitamin A can also work wonders for your immune system. Vitamin A promotes the production of white blood cells, particularly T cells, which eliminate viruses and bacteria from your body. Vitamin A also stimulates the production of special T cells called regulatory T cells. These help to reduce the risk of your body attacking its own healthy cells, which is what happens with some autoimmune diseases. Furthermore, vitamin A fortifies the linings of your respiratory, intestinal and urinary tracts, along with your skin and mucous membranes. It also sends additional immune cells there to prevent bacteria from entering your body and causing an infection.

Vitamin A is also involved in the maintenance of healthy skin by helping immature skin cells age properly into mature skin cells. It reduces sebum production, which can be problematic in oily skin. In fact, Isotretinoin is a common prescription-only vitamin A derivative used as a treatment for acne.

Vitamin A can also contribute to improved bone growth, cell division and cell differentiation. It even promotes reproduction and is a healthy supplement for people who are breastfeeding.

Food Sources of Vitamin A

Vitamin A is quite easy to come by naturally. Many of the most basic staples in our diets — meat, eggs, milk and cheese, for example — are excellent sources of vitamin A. Other specific animal sources have high vitamin A levels as well, such as kidney and liver. However, it's important to note that some of these foods have high cholesterol and saturated fat levels, so be sure to keep a healthy balance of these in your diet if you choose to eat them.

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Vitamin A exists as either preformed vitamin A or as provitamin A carotenoids. Preformed vitamin A is found in animal and dairy sources. Provitamin A carotenoids include beta-carotene and alpha-carotene, which your body converts into vitamin A and other derivatives. Beta-carotene is found in foods like carrots, pumpkins, sweet potatoes, cantaloupes, grapefruits, spinach, broccoli and apricots. As a general rule, the more vibrant the color of a fruit or vegetable is, the more beta-carotene it contains. As a bonus, you won't have to worry about the fat or cholesterol content in these foods.

Side Effects of Too Much Vitamin A

Getting the right amount of vitamin A in your diet shouldn't have any negative side effects. However, a vitamin A deficiency can lead to health issues over time. If you don't get enough vitamin A, you could develop vision problems. Plus, your immune system could weaken, leaving you susceptible to infectious diseases.

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Perhaps even more serious are the side effects of consuming too much vitamin A, also known as hypervitaminosis A. Initially, too much vitamin A can cause headaches, dizziness, nausea and even vomiting. Because vitamin A is fat-soluble, it tends to get stored in your liver if you consume too much of it, which can lead to liver problems and even liver failure. There's also evidence that getting excess vitamin A can cause osteoporosis and bone fractures.

In particular, pregnant people must be careful about their intake of vitamin A, as getting too much vitamin A can cause birth defects. Pregnant people shouldn't eat foods that are high in vitamin A, such as pate and fish liver oil. In general, babies and small children are more sensitive to vitamin A overdoses and deficiencies, so it's important to closely monitor their daily vitamin A consumption, too.

Taking Vitamin A: Daily Dosage Recommendations

According to the Institute of Medicine Food and Nutrition Board, most adult men should consume around 900 micrograms (mcg) of vitamin A per day, and women should have around 700mcg per day. The recommended daily intake is lower (750–770mcg per day) in pregnant people and higher (1200–1300mcg per day) for people who are breastfeeding.

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The daily dosage for children varies with age. From 0 to 6 months, infants should have 400mcg per day, after which they should consume 500mcg per day until they reach the age of 1. Children 1 to 3 years of age should get 300mcg per day, while those from 4 to 8 years of age need 400mcg per day. Those from 9 to 13 years old need 600mcg each day. Daily recommendations for children don't change based on gender.

These dosage requirements are general guidelines. Individuals may have differing daily recommendations for vitamin A, depending on their health status and lifestyle. Most people can get a sufficient amount of vitamin A simply by eating a balanced diet. Consult a doctor before taking any vitamin A supplements or changing from the recommended dosage for your age and sex.

In summary, it's important to be aware of the foods that'll give you an adequate supply of vitamin A. Provided you have a balanced diet, you might not need to take vitamin A supplements. Be aware of foods containing high levels of vitamin A, and avoid eating too much of these, particularly during pregnancy.

Resource Links:

https://medlineplus.gov/vitamina.html

https://bnf.nice.org.uk/treatment-summary/vitamins.html

https://www.nhs.uk/conditions/vitamins-and-minerals/vitamin-a/

https://ods.od.nih.gov/factsheets/VitaminA-Consumer/

https://ods.od.nih.gov/factsheets/VitaminA-HealthProfessional/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470929/pdf/nutrients-11-00681.pdf

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Hydrolyzed Collagen With Vitamin C Reviews

Hydrolyzed Collagen With Vitamin C Reviews

California Gold Nutrition, Hydrolyzed Collagen Peptides + Vitamin C, Type I & III, 250 Tablets

• Expiration Date: May 1 2023
• Date First Available: January 2 2018
• Shipping Weight:
• Product code: CGN-01178
• UPC Code: 898220011780
• Package Quantity: 250 Count
• Dimensions:

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Product overview

Description

• California Gold Nutrition Hydrolyzed Collagen + Vitamin C
• Type I & III Hydrolyzed Collagen Peptides Plus Vitamin C
• Support for Healthy Hair, Skin, Nail, Joints & Bones*
• Formulated to Contain: No Gluten, No GMOs, No Soy
• Produced in a 3rd Party Audited cGMP Registered (Certified) Facility
• 100% Gold Guarantee

Collagen is the primary structural protein found in joints, bones, skin, hair, nails and other connective tissues. It is responsible for maintaining the strength and elasticity/flexibility of these tissues found throughout the body.

California Gold Nutrition Hydrolyzed Collagen + Vitamin C complex contains unique, clinically researched, enzymatically hydrolyzed, low molecular weight Collagen Peptides with Vitamin C.

This product provides the fundamental building blocks for support of healthy hair, skin, nails, joints, & bones.* Taken as a dietary supplement, it provides the body with the raw materials needed to support the strength and integrity of body tissues.* Our specialty processed Collagen is Bovine sourced from Argentina and enzymatically hydrolyzed (broken down) into its component amino acid peptides in order to help ensure optimal absorption/bioavailability.

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The Collagen Connection

Benefits of Collagen Supplements

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Suggested use

Take 6 tablets daily, on an empty stomach at least 1 hour before or 2 hours after meals. Best when taken as directed by a qualified healthcare professional. Avoid taking with other foods containing protein as they may interfere with collagen absorption.

Other ingredients

Main Ingredients
Hydrolyzed Bovine Collagen Peptides, Vitamin C (as Calcium Ascorbate)

Other Ingredients
Stearic Acid, Magnesium Stearate, and Silicon Dioxide (Silica).

This product is not manufactured with milk, eggs, fish, crustacean shellfish, tree nuts, peanuts, wheat, soy or gluten. Produced in a third-party, audited and registered cGMP compliant facility that may process other products that contain these allergens or ingredients.

Warnings

Aroma and color may vary. Color shift is normal and cannot be avoided. Tablet chipping may occur and is normal as our tablets are not coated.

Double safety sealed, with outer shrink wrap film and inner bottle freshness seal. Best stored at controlled room temperature 20°C to 25°C (68°F to 77°F). Improper storage conditions, such as extended exposure to direct sunlight, high heat & humidity can cause product degradation over time.

Disclaimer

While iHerb strives to ensure the accuracy of its product images and information, some manufacturing changes to packaging and/or ingredients may be pending update on our site. Although items may occasionally ship with alternate packaging, freshness is always guaranteed. We recommend that you read labels, warnings and directions of all products before use and not rely solely on the information provided by iHerb.

Supplement Facts
Serving Size: 6 Tablets
Servings Per Container: About 42
	Amount Per Serving	%Daily Value
Calories	20
Protein	5 g	<1%**
Vitamin C (as Calcium Ascorbate)	60 mg	67%
Sodium	20 mg	1%
Hydrolyzed Collagen Peptides	6 g	†
**Percent Daily Values are based on a 2,000 calories diet. † Daily Value not established.

Hydrolyzed Collagen With Vitamin C Reviews

Source: https://uk.iherb.com/pr/california-gold-nutrition-hydrolyzed-collagen-peptides-vitamin-c-type-i-iii-250-tablets/77593

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