beta-glucan, cholesterol lowering, liver disease, reishi

Ganaderma lucidium polysaccharides

The original goal was to address two questions regarding the polysaccharides of Ganderma lucidium:

  1. What do they do?
  2. How are they digested and absorbed by the human gastrointestinal tract in the first place?  See Ganaderma lucidium tea to understand why we care.

One study I find truly incredible was performed by a group  from Mexico City (Meneses 2016).  Consistent with the mushroom harvesters I tagged along with, the Ganderma lucidium used in this study was isolated by tissue culture from a wild basidioma growing on dead tree in the State of Morelos, Mexico (2,300 m altitude).  The authors gave explicit details on how they propagated this sample.  The chemical composition details they gave of the 32% ethanol/water extracts from mushrooms cultivated on Quercus (oak) sawdust (Gl-1) and Quercus sawdust plus acetylsalicylic acid (10 mM; Gl-2) was truly amazing and sets new standards for the literature for DIYers to follow.

Meneses_supFig

Trolox is a water soluble analog of vitamin E.  Vitamin E is a scavenger of reactive oxygen species.

How do Ganoderma lucidium extracts compare to a popular cholesterol lowering drug?

Fifty-six male C57BL/6 mice, seven weeks old, weighing 26 g ± 0.50, were divided into seven groups of eight.  These authors used  two different doses of the two extracts with a popular cholesterol lowering drug.

  1. Ctrl:                 Control diet (AIN-93)
  2. Ch:                   High-cholesterol diet          (0.5% cholesterol)
  3. Ch+Sim:          High-cholesterol diet (0.5%) +  simvastatin (0.03 g/100 g), aka Zocor
  4. Ch+Gl-LD-1:    High-cholesterol diet (0.5%) + Gl-1 low dose (0.5%)
  5. Ch+Gl-HD-1:   High-cholesterol diet (0.5%) + Gl-1 high dose (1.0%);
  6. Ch+Gl-LD-2:   High cholesterol diet (0.5%) + Gl-2 low dose (0.5%)
  7. Ch+Gl-HD-2:   High-cholesterol diet (0.5%) + Gl-2 high dose (1.0%).

Figure 1 in the publication compares the nutritional content of each feeding group.  Each group was fed ad libitum for 43 d, including water.  Food consumption was recorded daily and weights were recorded biweekly.  During the last week feces were collected for bile acid analysis and microbiome speciation.   At the time of sacrifice, blood was collected for cholesterol and liver toxicity marker analysis.  The liver was also frozen for analysis of gene expression.

Gl_glut1a
There was no difference in food intake and weight gain between the seven treatment groups.

After showing that the mice ate the same amount of food and gained the same amount of weight, Meneses and coworkers turned their attention to total cholesterol (YC), triglycerides (TG) and low density lipoprotein plus cholesterol (LDL+C).  A general lowering of these parameters was seen by both the statin and the Ganaderma extracts.

Gl_glut1b
Different letter superscripts indicates differences in the means between groups at p<0.05. The last column is group effects.

The last two parameters in Table 2 were glucose and two liver enzymes that only appear in the blood when the liver is injured:  ALT and AST.  Cholesterol resulted in a slight increase in AST, but not ALT.    The statin and Ganaderma extracts lowered AST blood concentrations to that of the control.  Blood glucose was not changed by any treatment.

Gl_glut1c
Different letter superscripts indicates differences in the means between groups at p<0.05. The last column is group effects.

ALT: Alanine transaminase. is a marker of liver injury.   The high cholesterol diet causes an increase in ALT that is not significant at p<0.05.  Both doses of Gl-1 and the high dose of Gl-2 significantly decrease the ALT enzyme in plasma as a result of a high cholesterol diet.

AST: Aspartate transaminase is another marker of liver injury.

 

Choleserol

Meneses_Figcholesterol
Only the two high doses of the Ganaderma extract return the liver cholesterol concentrations to that statistically the same as the control

TG: Triglycerides. 

While the high cholesterol didn’t seem to affect blood TG, both Gl extracts were more effective in lowering liver TG than Zocor/simvastatin.

Meneses_TG
The statin was unable to lower liver triglyerides to a level statistically different from cholesterol alone.

LDL-C: Low-density lipoprotein cholesterol.  Zocor was ineffective in bringing LDL cholesterol back to control levels.  The high dose of  Gl-2 was able to bring the rats on a high cholesterol diet back to control LDL levels.

2A:  Lipogenic genes

Meneses_2A.png

Srebp1c, sterol regulatory element binding protein transcription factor 1c is regulated by hepatic cholesterol  which is a ligand for  the liver X receptor (LXR) transcription factor.  Srebp1c regulates the expression of lipogenic genes.

Acaca, actyl CoA carboxylase mediates the conversion of AcCoa to malonyl-CoA.

Fasn, fatty acid synthase catalyzes the formation of long-chain fatty acids from acetyl-CoA, malonyl-CoA and NADPH.

2B: Genes associated with cholesterol metabolism.

Meneses_2B.png

Srebp2 regulates gene expression linked to cholesterol synthesis such as Hmgcr and Ldlr.

Hmgcr,  3-hydroxy-3-methylglutaryl coenzyme A reductase, is a rate limiting enzyme in the process of cholesterol biosynthesis.    Simvastin/Licor is an inhibitor of Hmgcr.

Ldlr,  low-density lipoprotein receptor, regulates the liver tissue uptake of LDL-C from the plasma via endocytosis.  .

In Figure 3 of the 2016 publication, Meneses presented  some Western blots of liver proteins backing up the increases they saw in mRNA transcripts.

4A: Genes associated with cholesterol excretion.

The authors asked how a high cholesterol diet and treatment wtih Zocor/simvastatin  and Gl extracts affected excretion into the feces.

Meneses_4A
The four different doses of the Gl extracts and the statin seemed to be take gene transcription to some level between the control (b or c) and cholesterol diet without intervention (a).

4B & C:  Gl extracts result in more cholesterol and bile acids being excreted in feces

Meneses_4B&amp;C
Cholesterol exits teh body in the feces.

Effect of experimental diets on intestinal phyla and the Lactobacillus genus

This will be covered in another post.

Gl_glut1d
Cholesterol and bile acids are released by the gall bladder into the duodenum of the small intestine. where they may be reabsorbed.

If we mammals cannot digest  β-glucans, how are they exerting their beneficial affect?  They probably are not simply chelating cholesterol and bile acids because they are changing gene transcription.  The answer may lie in the colon and the bacteria that can ferment β-glucans into compounds that will alter gene transcription.

A role for the polyphenols?

It should be noted that the triterpenes in Gl extracts are themselves cholesterol derivatives. Meneses and coworkers cited references in the literature finding an association in the polyphenols of Gl and improved lipid profiles.

 

References

Chang CJ, Lin CS, Lu CC, Martel J, Ko YF, Ojcius DM, Tseng SF, Wu TR, Chen YY, Young JD, Lai HC.(2015) Ganoderma lucidum reduces obesity in mice by modulating the composition of the gut microbiota. Nat Commun. 6:7489.  PubMed

Meneses ME, Martínez-Carrera D, Torres N, Sánchez-Tapia M, Aguilar-López M, Morales P, Sobal M, Bernabé T, Escudero H, Granados-Portillo O, Tovar AR. (2016) Hypocholesterolemic Properties and Prebiotic Effects of Mexican Ganoderma lucidum in C57BL/6 Mice. PLoS One.11(7):e0159631  PubMed

 

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