A critical lipoprotein receptor reduces metabolic disorders brought on by low testosterone

June 2, 2014 § Leave a comment

A mouse from the Kypreos laboratory study about the role of the low density lipoprotein receptor in modulating testosterone's effects.

A mouse from the Kypreos laboratory study about the role of the low density lipoprotein receptor in modulating testosterone’s effects.

 Testosterone is the male sex hormone involved in sex differentiation, libido and erectile function. It’s also known to play a role in metabolism and influence obesity, type 2 diabetes and other metabolic disorders. But how testosterone participates in various metabolic pathways is not clear. In a paper just published in the Journal of Lipid Research, investigators demonstrate that the effects of testosterone on metabolism may be altered by the low density lipoprotein receptor, a critical protein for the transport of lipid-modified proteins and the regulation of blood cholesterol levels.

The study is important, says lead author Kyriakos Kypreos at University of Patras Medical School in Greece, because it reveals “a novel role of the LDL receptor as a switch for processes associated with testosterone-induced metabolic alterations, such as body weight and body fat content, energy metabolism, and glucose tolerance.” Based on this finding, Kypreos adds that scientists can now focus on drugs to treat metabolic disorders that modulate the number of functional LDL receptors on cells.

Kypreos and colleagues have a longstanding interest in metabolic disorders in which testosterone is involved. Testosterone deficiency in men, called hypogonadism, is considered a primary risk factor for a number of disorders. These disorders include obesity, insulin resistance, and dyslipidemia, a condition where LDL-cholesterol and total cholesterol levels in blood are raised.

Kypreos says he and his colleagues came across research that suggested that the LDL receptor was an important receptor in diet-induced obesity.  There is also research that shows that mutations in LDL receptor cause coronary heart disease and dyslipidemia.

Putting it all together, Kypreos and colleagues decided to investigate the potential involvement of the LDL receptor superfamily in the metabolic actions of testosterone. The investigators used genetically engineered male mice that were missing the LDL receptor. They surgically castrated these mice to see how low testosterone levels and a lack of LDL receptor affected metabolism. They feed the mice a high-fat diet “to mimic the human situation where obesity develops as a result of disruption of homeostasis between food intake and energy expenditure,” explains Kypreos.

The investigators discovered that the LDL receptor “is a main switch of testosterone actions on body metabolism,” says Kypreos. The receptor helps testosterone trigger those pathways involved in maintaining blood sugar and triglyceride levels. The investigators’ data also suggest that the receptor affects how testosterone activates fat burning in white adipose tissue. Kypreos says one of the group’s aims now is to search for “molecular targets for new pharmaceuticals that will promote fat burning through thermogenesis as a treatment of obesity and obesity-related complications.”

Gut bacteria may be a source of male steroid hormones

June 25, 2013 § Leave a comment

Cortisol tuns on genes to make an enzyme that converts glucocorticoids into androgens by Clostridium scindens in the gut.

Cortisol tuns on genes to make an enzyme that converts glucocorticoids into androgens by Clostridium scindens in the gut.

Looks like there is more than one fount for male steroid hormones in the body. In a paper recently out in the Journal of Lipid Research, researchers show that a bacterial species converts glucocorticoids into androgens, a group of male steroid hormones. The implication is that the host endocrine system may not be the only source of androgens and other regulatory molecules: The gut microbiome may be another.

Phillip Hylemon at the Virginia Commonwealth University explains that there has been evidence since the 1960s that secondary bile acids, which are microbial products made from the primary bile acids secreted by the gallbladder, are associated with gastrointestinal diseases, such as colon cancer and cholesterol gallstones. “A small number of microbes inhabiting the (gastrointestinal) tract are the sole source of these molecules,” he explains.

His group and others have worked out how the bacterium Clostridium scindens  carries out the primary to secondary bile acid transformation. But it turns out C. scindens also can make androgens from glucocorticoids. Why is this important?

Hylemon explains that, in the gut, androgens can be further modified by other members of the gut microbiota to make testosterone-type derivatives. “It is possible that these steroid metabolites interact with host nuclear receptors or other gut organisms. In males, for instance, the prostate gland is against the rectum wall. Therefore, androgens produced by gut bacteria are capable of passively diffusing into this organ, perhaps altering the physiology of cells in the prostate,” he says.

C. scindens is the only bacterium in the human GI tract known to convert glucocorticoids into androgens, but how does it do it?

Hylemon and colleagues decided to use high-throughput nucleic acid sequencing to identify the genes encoding the enzymes involved in this biotransformation. They knew the genes were turned on by cortisol, a stress-induced steroid hormone. By comparing levels of mRNA from C. scindens cultivated in broth with and without cortisol, the investigators reasoned that they would be able to identify candidate genes.

They identified a cluster of genes that encode a transketolase whose sequence is different from those involved in carbohydrate metabolism. A question now is if the C. scindens transketolase evolved to carry out the biotransformation of glucocorticoids into androgens specifically.

The implication of the work is that a bacterium like C. scindens could play an important role in the endocrine system. “It is generally agreed in the field that the gut microbiota constitute a virtual organ. We believe that, like other organs in the body, this organ has specialized cells that produce hormones that may be derived from host-synthesized bile acids and steroid hormones,” says Hylemon. Because the gut microbiome can produce hormones, Jason Ridlon, the first author on the paper, says, “we consider the gut microbiome to be an endocrine organ.”

The investigators now would like to see if androgen-like molecules produced by the gut microbiome have the same effects on physiology as do the ones generated by the host endocrine system. Hylemon says, “Our next step is to screen bacterial-generated bile acids and steroid hormone metabolites for their ability to bind to and activate host G-protein-coupled receptors and nuclear receptors.”

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