Sunday, August 26, 2012

Cholesterol

Functions of Cholesterol

Cholesterol has several essential functions in the body: 

  • It is required for cell membranes to maintain membrane integrating and regulate fluidity
  • It is used to make myelin, which enables the electrical signals (action potentials) in neurons to move faster
  • It is used to make bile to digest lipids (fats, fat-soluble vitamins, etc)
  • It is used to make steroid hormones such as aldosterone (salt and water balance), vitamin D, corticosteroids (cortisol) and the sex hormones (testosterone, dihydrotesterone, estrogen and progesterone)  (see here)

This is why not having enough cholesterol can be a problem, as seen in Smith-Lemli-Opitz syndrome, a genetic disorder of impaired cholesterol synthesis, resulting in malformations, intellectual disability and other problems.

* Other living organisms use sterols.  Plants use phytosterols (stigmasterol, campesterol, beta-sitosterol) and fungi use ergosterols.

Where Cholesterol Comes From

Our body synthesises about 1,000 mg of cholesterol through a series of biochemical steps (see here) that ultimately converts 2 acetate molecules (carried by Acetyl CoA) to cholesterol.  Acetate can come from any macronutrient when they undergo aerobic metabolism to be burned for energy*.

Most of the cholesterol in our bloodstream is synthesised, but we can also get some from dietary sources.  Cholesterol levels and synthesis is regulated, when we absorb cholesterol from foods our body simply downregulates cholesterol synthesis.  Even the Australian dietary guidelines mention this**.  

“Eating cholesterol does not necessarily increase cholesterol in human blood plasma because when it is absorbed the liver tends to reduce its own endogenous cholesterol synthesis. About half the body’s cholesterol is made in the body from acetate.”  


* The standard cholesterol-lowering drugs are called 'statins', which are HMG-CoA reductase inhibitors.  HMG-CoA reductase is an enzyme that catalyses the third step of cholesterol synthesis.  Statins also inhibit the synthesis of other molecules in the cholesterol synthesis pathway, such as coenzyme Q10, squalene, isoprene and rho activation, which may be responsible for some of the adverse side-effects of statins 

** Let’s say an average person has a total cholesterol of 200 mg/dl and 5.0 litres of blood, so they have 10 grams of cholesterol in the bloodstream.  It’s easy to see how most people’s serum cholesterol is relatively unaffected when eating 300-400 mg of cholesterol (the Australian average), in other words 3-4% of their blood levels. 

Lipoproteins Transport Cholesterol

Cholesterol is fat-soluble and therefore has difficulty travelling throughout the bloodstream, which is mostly water.  The solution to this problem is to have a protein transporter (protein is water soluble).  High density lipoproteins (HDL), low density lipoproteins (LDL), intermediate density lipoproteins (IDL), very low density lipoproteins (VLDL) and chylomicrons transport cholesterol and other lipids (fatty acids, triglycerides, fat soluble vitamins) throughout the body (chylomicrons transport recently digested lipids from the small intestine)*.


HDL is often referred to as ‘good’ cholesterol and LDL as ‘bad’ cholesterol.  But HDL and LDL aren’t different types of cholesterol, rather they are different types of lipoproteins.  There is only one kind of cholesterol, C27H46O.  The reason why HDL is considered good cholesterol and LDL as bad cholesterol is because the amount of cholesterol in HDL particles (HDL-C) is negatively associated with cardiovascular disease and the amount of cholesterol in LDL particles (LDL-C) is positively associated with cardiovascular disease.  But it is quite simplistic to think of HDL as good and LDL as bad.  LDL carries out important functions such as distributing cholesterol, triglycerides and fat soluble nutrients.

* Other fat soluble things in the body have protein transporters.  For example the sex hormones are transported by sex hormone binding globulin (SHBG) 

** Sometimes people say ‘cholesterol is a fat’, which is wrong.  Cholesterol is a type of lipid.  Fatty acids, triglycerides, fat soluble vitamins and phospholipids are lipids as well.  Cholesterol is not a fat and looks nothing like one (see here) 

Further Reading:
(1) The straight dope on cholesterol – Part I
(2) The straight dope on cholesterol – Part II
(3) Cholesterol and Health — Functions and Foods
(4) The Full Story: Why Eggs Do Not Cause Cardiovascular Disease

Sunday, August 19, 2012

Cancer

Summary

DNA damage occurs every day, but we have certain enzymes to repair this damage.  Replicating damaged DNA results in DNA mutations or cell death, but not all DNA mutations lead to cancer.  Only DNA mutations that encode for genes that carry out functions such as controlled cell death, cell survival and cell proliferation can lead to cancer.

Certain viral infections can be an alternative route to cancer instead of DNA mutations.  Viral RNA often contains genes that promote cell proliferation and inhibit cell cycle checkpoints to increase their virulence, but can have the side effect of promoting cancer.  Some viruses (called retroviruses) replicate themselves by injecting their RNA into the host cell and making the host cell change the viral RNA into DNA and then has the host cell incorporate the viral DNA into the host cell’s genome.

Tumour cells need further mutations to survive in the bloodstream and become metastatic.  Once tumour cells become metastatic they are very difficult to get rid of.

Mitochondrial dysfunction is likely to be the main cause of cancer since: carcinogens also impair mitochondrial function; mitochondrial and mitochondrial DNA is more vulnerable to nuclear DNA and therefore more likely to be damaged first; mitochondrial dysfunction increases reactive oxygen species, inflammation, genome instability and signals hypoxia.  Mitochondrial dysfunction can cause the Warburg effect, where tumour cells preferentially metabolise glucose to lactate for energy, even in the presence of oxygen (aerobic glycolysis), which is advantageous to the tumour cells for several reasons

Another cause of metastasis is from when tumour cells merge with macrophages, which allows the tumour cell to better evade the immune system and infiltrate tissues

Pro-inflammatory cytokines have many effects that promote cancer such as oxidative stress, angiogenesis, cell proliferation and inhibiting cell death and the adaptive immune system.  Inflammation is strongly associated with cancer, particularly in the same region as the inflammation.  For example: IBD and colorectal cancer, thyroid cancer and Hashimoto’s thyroiditis and H. pylori infection and gastric cancer.

A role of the immune system is to kill cancer cells.  Mice lacking certain immune cells can develop spontaneous tumors.  When these tumours are transplanted into healthy mice they are rejected by immune system.  People with weaker immune systems are more likely to have worse prognosis


Some Strategies for Cancer

This is for informational purposes only and is not meant to diagnose or treat any medical condition.

The Conditions that Promote Cancer

Reduce/manage: mitochondrial dysfunction (see Mitochondrial Dysfunction, mainly the second half); chronic inflammation (see Causes of Inflammation); and immune suppression (which will also help with viral infections).

For immune function the following things should help: vitamin A [1], vitamin D [2], zinc [3], nutrient density in general [4], reducing/managing stress better [5] [6] [7] and getting good sleep (at the appropriate time) [8] [9]

* Vitamin A [10] and vitamin D [11] [12] [13] also have other anti-cancer effects and the combination is effective at killing cancer cells [14].  Vitamin K2 works synergistically with A and D [15], has anti-cancer effects [16] [17] and in a small trial (n=40) megadoses (45mg/d) of K2 reduced the risk of hepatocellular carcinoma by 80% in women with liver cirrhosis [18]

The Ketogenic Diet for Cancer

A ketogenic diet (moderate protein, very high fat, very low carb, roughly 15:80:5) denies the tumour cells of glucose and provides ketones which can be used fuel by many tissues but usually not by tumour cells.  Ketogenic diets help to retain lean mass with cancer cachexia.  Ketogenic diets decrease inflammation [19] and increase AMPK [20], which: stimulates mitochondrial biogenesis [20]; increases DNA repair enzymes (!) [21]; lowers IGF-1 and inhibits mTOR; inhibits lipogenesis in tumour cells (they need a lot of lipids for growth); inhibits cell division; increases oxidative stress in tumours [22]; and inhibits aromatase [23]

Sunday, August 12, 2012

Immune Suppression and Cancer

While mitochondrial dysfunction, chronic inflammation and viral infections can initiate cancer and are quite common, only some people get cancer.  With infections for example: 90% of people are infected with EBV but only 2-6% of those infected will develop an EBV related cancer [1] and roughly 50% of people are infected with H. pylori but only 1-2% of those infected develop gastric cancer [2].  With chronic inflammation an example is that 43% of people with ulcerative colitis develop colorectal cancer after 25-35 years [1].  This suggests other factors are involved.  At least in the case of EBV and H. pylori infections, developing a cancer tends to require one to have elevated pro-inflammatory cytokines [2] or to be immunocompromised [3], as CD8+ T cells are protective against cancer [4] 

A major factor is probably the state of the immune system.  CD8+ T cells (cytotoxic T cells) are a part of the adaptive immune system and are responsible for anti-tumour immunity.  They kill infected and tumour cells, prevent the development of tumours and inhibit tumour progression.  Mice lacking cytotoxic T cells and natural killer cells* can develop spontaneous tumors.  When these tumours are transplanted into wild type mice they are rejected by the cytotoxic T cells [4].  People with HIV/AIDS or organ transplants have a higher risk of cancer, mostly from infectious causes [5] and people with more cytotoxic T cells tend to have less metastasis, less disease recurrence and longer survival [2]. 

Tumour cells try to protect themselves from the immune system by generating T regulatory (Treg) cells, which inhibits the adaptive immune system, produces IL-10 (an anti-inflammatory cytokine) and increases angiogenesis.  Since tumour cells express ‘self’ antigens Treg cells will frequently infiltrate and suppress immunity to protect tumours.  As the tumour progresses more and more Treg cells are made.  Treg cells are associated with poor patient outcomes [2] [6] [7] 

Senescent/old cells can inhibit their cell cycle and release several chemicals, some are pro-tumour tumours, others are anti-tumour.  The anti-tumour chemicals increase immune activity to facilitate clearance of the senescent cell, which stops it becoming cancerous.  If immune function is poor these cells don’t get cleared effectively so people with immunosuppression have more senescent cells.  This results in more cells with high oxidative stress, elevated pro-tumour signalling and prevents younger cells from taking their place thereby speeding up the aging process [6] [8

* Natural killer cells are like cytotoxic T cells, but are part of the innate immune system, rather than the adaptive immune system

Sunday, August 5, 2012

Inflammation and Cancer

Cancer is associated with inflammation and elevated levels of inflammatory markers.  Inflammation increases genetic instability, DNA damage and cell proliferation and promotes tumour development and growth [1] [2]. 

Pro-inflammatory cytokines (such as IL-1, IL-6, TNF-α) are elevated in tumour cells from the earliest stages of development.  They can increase tumour progression and PTP1B, promote angiogenesis, growth and proliferation of tumour cells and inhibit apoptosis of tumour cells.  Tumour cells produce and secrete IL-1 and TNF-α for these reasons [1] [2] [3] [4] [5]. 

NFκB can be induced by pro-inflammatory cytokines (IL-1, TNF-α), inflammatory substances (LPS, ROS, ionising radiation) and hypoxia.  NFκB activates gene expression for pro-inflammatory cytokines, enzymes for pro-inflammatory eicosanoids (such as COX2), adhesion molecules, angiogenesis, inhibiting apoptosis.  NFκB promotes the proliferation and survival of malignant cells and metastasis and inhibits the adaptive immune system [1] [2] [4] 

People with chronic inflammatory diseases are more like to have cancer in the inflammed tissues:

  • People with IBD are 5-7 times more likely to develop colorectal cancer [1]
  • 43% of people with ulcerative colitis develop colorectal cancer after 25-35 years [1]
  • Papillary thyroid cancer is associated with Hashimoto’s thyroiditis and Grave’s disease (two autoimmune thyroid diseases) [5]
  • H. pylori infection is associated with gastric cancer and gastric mucosal lymphoma [2], in particular the degree of inflammation from H. pylori infection is associated with gastric cancer [6]
  • Prostatitis is associated with prostate cancer [2]

Further evidence to support the role of inflammation in cancer: 

  • In an animal model of IBD (from IL-10 deficiency) there were 4-5 times more DNA mutations [2]
  • The development of hepatocellular carcinoma in mice carrying HBV genes is associated with inflammation and liver damage [7]
  • Increasing inflammatory cells or pro-inflammatory cytokines promotes the development of tumour cells [2]
  • Levels of DNA oxidation (8-oxo-dG) are increased in those with chronic inflammatory diseases and chronic infections [8]
  • People with IL-1 producing tumours tend to have poorer outcomes [1]
  • In an animal model of IBD colorectal cancer can be inhibited by blocking TNF-α [1]
  • Blocking inflammatory signals (such as IL-1, TNF-α, NFκB and STAT3) decreases the incidence and spread of cancer [1]
  • Anti-inflammatory drugs such as NSAIDs are associated with a reduced risk of developing some cancers, relapse, new tumours and mortality relating to these cancers [1] [2]