Going beyond Blood biomarkers to optimize cholesterol production
Abstract
Globally high cholesterol impacts around 39% of the adult population & is considered to be one of the leading biomarkers for cardiovascular diseases. Over the last few decades, the healthcare community has has been focussed on tracking Low Density Lipoprotein Cholesterol(LDL-C), High Density Lipoprotein Cholesterol(HDL-C), Total Cholesterol(TC), Triglycerides level (TG) & APOB-100 to suppress cholesterol by adopting pharmaceutical approach rather than deep diving into biological dysregulation that causes elevated cholesterol levels. LDL has been renamed as bad cholesterol & HDL as good cholesterol without having a clear cut understanding of the key role LDL plays in a number of cellular processes.
However the system has not been able to find answers to questions such as
- What molecular pathways upregulation or overexpression of these plasma level biomarkers?
- What are the interventions to regulate them? Are there standard interventions or married with an individual’s unique biology?
Have you ever wondered why?
The healthcare system has missed out studying the role of 99% of biology- human microbiome in elevation of cholesterol levels. This expert opinion article discusses the role of microbiome & metabolites produced by them in regulating cholesterol levels.
Cholesterol- our oldest & life saving companion
There is a saying- there is no life without cholesterol. Cholesterol is a lipid. It is synthesized by every cell inside the body. Every cell needs cholesterol for performing various cellular processes. Some cells do not have enough cholesterol to perform their job & hence borrow for other cells/tissues such as the liver. Therefore some cells are net exporters while others are net importers. Therefore cholesterol has to travel from one cell to another via the circulatory system.
Since Cholesterol is not soluble in water, it is packaged with a protein called lipoprotein. The protein portion of lipoprotein is called apolipoprotein which acts on transport & metabolism of lipoproteins. The two most abundant apolipoprotein are APOB & APOA. APOB-100(a longer version of APOB) acts as an outer shell to transport cholesterol. Cholesterol is packaged with very low density lipoprotein(VLDL) & low density lipoprotein(LDL) which travels to different cells via this vehicle for cells to perform cellular processes.
The reverse cholesterol transport process.
Cells, after utilizing cholesterol for various biological processes, export the excess cholesterol back to the liver through reverse cholesterol transport process from where it is redistributed to other cells for various biological processes or excreted from feces. These biological processes include synthesis of Vitamin D, bile acid metabolism, regulating of sex hormones, brain functioning & more.
During this reverse cholesterol transport process, liver & intestine synthesise apolipoprotein APOA-1 which contains 70% of protein content of HDL-C. APOA-1 enters the bloodstream & interacts with peripheral tissues such as Heart. In vein & arteries, APOA-1 interacts with receptors of various cell types. The interaction with the protein makes cholesterol & some lipids move to APOA-1 which results in formation of nascent HDL particles-pre-β HDL. Subsequently, this interacts with receptor SR-B1, thereby forming more matured cholesterol- HDL-c.
Matured HDL-c interacts with a receptor in the liver which facilitates transfer of cholesterol back into the liver from where it is redistributed to other cells for performing various processes as mentioned above.
The role of Gut Microbiome in programming cholesterol for either health or disease
This is a normal process for putting cholesterol to work for performing various biological processes to promote our health. However, wrong dietary choices can cause gut microbiome( 38 trillion microbes living inside the gut that account for 99% of genes expressed inside our body, 57% of cells are microbial) dysbiosis making microbes overexpress virulence genes & secrete pro-inflammatory metabolites &/or under-expressing genes that promote production of beneficial metabolites.
Some of metabolites that can trigger overproduction/less clearance of VLDL/LDL &/or under-regulation of HDL-c include
- Short Chain Fatty Acids(SCFA) Production: Certain microbes consuming fiber from our diet produce SCFA such as butyrate, propionate & acetate which are associated with increased expression of genes that lowers TG level & clears VLDL & LDL levels. Besides, Butyrate inhibits inflammation driven decrease in APOA-1. Gut dysbiosis, leads to low butyrate production, thereby leading to increased VLDL & LDL production & underexpression of APOA-1. This elevates cholesterol levels.
- Indole-3-propionic acid (IPA): Certain gut microbes metabolize tryptophan & synthesize it in IPA which is said to clear VLDL & LDL & inhibit development of atherosclerosis. When the gut microbiome is imbalanced , it could lead to low IPA production , thereby leading to overexpression of genes that inhibits clearance of LDL.
- Trimethylamine-N-oxide (TMAO) Production: In case of gut dysbiosis, certain Proteobacteria can metabolize choline, L-carnitine & Lecithin & synthesize them into TMA which when passed through iverl gets converted into TMAO. This harmful metabolite is said to inhibit reverse cholesterol transport process & impaired bile acid synthesis
- Lipopolysaccharides(LPS) Production: LPS is an endotoxin produced by Gammaproteobacteria which causes adiposity & triggers onset & progression of type 2 diabetes & cardiovascular diseases. When gut microbiome is imbalanced, there is increase in LPS production which suppressed APOA-1 thereby inhibiting LDL clearance
- P-cresol Production: P-cresol is a pro-inflammatory metabolite produced when specific gut microbes ferment amino acid L-tyrosine. This metabolite is not only connected with progression of chronic kidney disease but also increases LDL uptake.
- Phenylacetylglutamine(PAG) Production: PAG is a microbial byproduct of certain microbes metabolizing amino acid L-phenylalanine which is associated with increased triglyceride levels & high risk of coronary artery disease.
To summarize
Cholesterol is essential for various cellular processes & focus should not be on suppressing cholesterol. Rather than tracking LDL-C, HDL-C, TC & APOB-100 levels which does not give a clear picture of the underlying cause of high cholesterol, diagnosis should focus on decoding & fixing our gut microbiome functions to promote secretion of anti-inflammatory metabolites & suppress production of pro-inflammatory metabolites
We at Genefitletics offers India’s first & only system biology + AI platform that measures & analyzes gut & oral microbial genes expression to determine the root cause of various chronic diseases including cardiovascular diseases & inform disease modifying precision nutrition interventions
Our unique prediction model: VASCOMATH- measure hard to detect molecular signals to predict risk of onset & progression of Cardiovascular Diseases. More details here:www.genefitletics.com
Citations below
https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1271001/full#B35
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962737/
https://www.sciencedirect.com/science/article/abs/pii/S156757692300869X
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290464/
https://pubmed.ncbi.nlm.nih.gov/35893593