The importance of the liver for overall health
The liver is the second largest organ (after the skin) of the human body and probably has the most diverse metabolic activity. It is part of the digestive system and performs many vital functions. Many of these processes happen on membranes, either the plasma membrane or internal membranes of organelles, which are thought to add up to 33,000 square meters of the surface area [Kidd, 1996]. This is one probable reason as to why supporting healthy membranes through phospholipids may have such a protective effect for the liver.
The blood supply of the liver is different from other organs in that it receives oxygenated blood through the hepatic artery, but also deoxygenised blood from the digestive tract through the hepatic portal vein which is rich in absorbed nutrients and other, potentially harmful, substances which have been absorbed from the intestines. From the hepatic artery and portal vein, blood flows into sinusoids which are endothelium-lined spaces (rather than capillaries), from there into central veins and on into the hepatic vein towards the heart and circulation around the body. In the sinusoids oxygen, nutrients and other substances are absorbed into the hepatocytes (liver cells) lining them, whilst compounds manufactured in the liver and nutrients needed elsewhere are excreted into the blood [Tartora and Grabowski].
This hepatic circulation system is the main reason for the so-called “first pass effect” of drugs, the concentration and bioavailability of which can be greatly reduced due to the liver metabolising it post absorption [Pond and Tozer, 1984].
The sinusoids also contain Kupffer cells which are part of the immune system. As specialised macrophages, they “tidy up” old white and red blood cells, bacteria and other foreign compounds.
Bile production
One of the main digestive functions of the liver is in producing bile which is needed for fat digestion. In an adult, the liver produces 800-1000ml bile a day, a yellow, green or brownish liquid which consists of water, bile acids, bile salts, cholesterol, lecithin, bile pigments, and various ions. Bile is continuously produced by the liver and stored in the gallbladder from where it is excreted into the small intestine as a bolus when fat-containing food arrives. Bile is slightly alkaline which helps neutralise stomach acid in the small intestine.
The role of bile in the digestive process is to emulsify dietary fat to increase the surface area and thus allow pancreatic lipases to break down triglycerides ready for absorption. As fat-soluble vitamins (A, E, K, and D) are absorbed together with fats, bile also plays an important role in their absorption.
The main bile pigment, which gives faeces its normal brown colour, is bilirubin, a breakdown product of old hemoglobin which is excreted with bile.
Detoxification
The liver is one the two main organs of detoxification, the other one being the intestinal mucosal wall. We are constantly exposed to toxins, exogenous ones (“xenobiotics”), as well as endogenous ones, like by-products of our normal metabolism or old hormones. It is estimated that in 2002 alone more than 4 billion kilograms of toxins were released into the environment in the US. This unprecedented exposure to exogenous toxins puts an enormous strain on our livers to get rid of them before they can play havoc in our bodies [Liska D et al, 2010].
Detoxification (or “biotransformation”) processes are catalysed by enzymes, such as the Cytochrom P450 enzymes, which are membrane-bound and usually located on the inner membrane of either mitochondria or the endoplasmatic reticulum.
Optimally functioning detoxification (and elimination) is crucial for our whole physiology and supporting liver function, therefore, a key to good health.
Carbohydrate metabolism
The liver plays a key role in keeping blood glucose levels within a narrow healthy range. It does so by releasing glucose from glycogen stores and gluconeogenesis when blood glucose is low, and converting glucose to glycogen and triglycerides for storage when blood glucose is high. It also converts other sugars, like fructose and galactose to glucose.
Protein metabolism
In the liver amino acids have their amino group removed so that they can be either used for energy production or converted to fats or carbohydrates. This creates ammonia which is converted to the less toxic urea which can be excreted through the kidneys.
The liver also manufactures many blood proteins such as albumin, globulins, prothrombin and fibrinogen, and therefore plays an important role in blood clotting and transport of many compounds in blood.
Fat metabolism
Many processes of fat metabolism take place in the liver, including the breakdown of fatty acids for energy production, storage of triglycerides, synthesis of cholesterol and lipoproteins, which transport fatty acids, triglycerides, and cholesterol to and from the cells in the body.
Storage and metabolism of nutrients
Many vitamins, including vitamin B12 and the fat-soluble vitamins A, D, E and K, and minerals, including iron and copper, are stored in the liver. This is why the liver is such a nutrient-dense food.
Alongside the skin and kidneys, the liver also plays an important role in the activation and metabolism of vitamin D.
Cell membranes
Healthy membranes are vital for the functioning of cells, and with that for any tissue and organ in our bodies. Cell membranes carry out many cellular functions, including barrier function, transport, cell signaling and communication, secretion and recognition. Looking at all these functions which are carried out by the cell membranes it becomes clear that the membrane, rather than the nucleus, is the “brain” of the cell, or the “mem-brain” as Bruce Lipton calls it [Lipton, 2005].
It is, therefore, no surprise that supporting healthy membranes through nutrition can have a very wide range of benefits, from the liver and cardiovascular function to anti-ageing and energy metabolism. So let’s look at the structure and function of membranes in more detail, to better understand their vital importance for our health and wellbeing [Nicolson, 2014].
Cell membrane structure
Lipid bilayer
The plasma membrane forms the barrier between the inside and outside of the cell, separating the cytoplasm and the extracellular space. Membranes also form various intracellular organelles, including
- The mitochondria – the powerhouses of the cell.
- The endoplasmatic reticulum (ER) – the factories where proteins, fats, including phospholipids, steroids, and many other compounds are synthesised. This is continuous with the nuclear envelope which is also membrane-based. In liver cells, this is also where many of the detoxification pathways take place.
- The Golgi apparatus – the logistics centre where proteins and other molecules are received from the ER, modified and transported to their destinations. Lysosomes – the rubbish collection service with reservoirs of hydrolytic enzymes which are important in autophagy, the destruction of dysfunctional or unnecessary cell components. [Tartora and Grabowski, 2000]
The Fluid Mosaic Membrane Model (FMMM), proposed by Singer and Nicholson in 1972 [Singer and Nicolson, 1972], is still the accepted model for cell membranes and explains their many features and functions. The structure of such membranes is based on two back-to-back layers of phospholipids into which other lipids, like cholesterol and glycolipids, and proteins are embedded. A typical plasma membrane is made out of approximately 50% lipids and 50% proteins.
Phospholipids are amphipathic, that is they have a polar, hydrophilic (“water-loving”) head and a non-polar, hydrophobic (“water-fearing”) tail. The head is made of a phosphate group to which another molecule, such as choline in phosphatidylcholine, is attached. This head is attached to a glycerol backbone, which is also ester-linked to two fatty acids, forming the non-polar part. In a “like seeks like” fashion, the non-polar lipid tails orient themselves spontaneously towards each other whilst the polar heads point to the outside, forming a lipid bilayer. Phospholipids account for about 75% of membrane lipids. Other lipids include cholesterol, sphingolipids and glycolipids [Kidd, 2002; Nicolson and Ash, 2017; Tartora and Grabowski, 2000].
The length and degree of saturation of the fatty acid tails within the lipid bilayer is crucial for the fluidity of the membrane. The double-bonds of unsaturated fatty acids induce structural kinks which result in a higher fluidity of the membrane, whereas saturated fatty acids, which appear as straight tails, can be packed more tightly, leading to a more rigid membrane [Nicolson and Ash, 2017; Janmey and Kinnunen, 2006].
The fatty acid composition of membranes is important for their functions and varies between different types of membranes. For example, plasma membranes tend to have a higher proportion of cholesterol than the membranes of organelles [Nicolson, 2014; Shevchenko and Simons, 2010]. Membranes are also characterised by an asymmetrical distribution of both lipids and proteins, for example, phosphatidylcholine, a phospholipid with choline attached to the phosphate group, tends to be more common on the outside of plasma membranes than on the inside [Shevchenko and Simons, 2010].
Phosphatidylcholine is the most abundant phospholipid in eukaryotic cell membranes, accounting for more than half of all phospholipids. Other important phospholipids are phosphatidylserine, phosphatidylinositol, phosphatidylethanolamine, and phosphatidylglycerol. The phospholipid composition of the membrane affects the curvature of the bilayer and with that structure and function [Janmey and Kinnunen, 2006].
It was initially thought that all cell membrane compounds can freely move laterally. This aspect of the FMMM was later revised to a model whereby the lipid bilayer contains domains with low lateral mobility. These domains contain fluid and structured lipids, and integral proteins which extend into or through the bilayer, peripheral proteins, and membrane-associated protein complexes which sit on top of the bilayer and form a cytoskeleton and an extracellular matrix. The formation of these domains allows for specialised functions of particular regions within the membrane [Nicolson, 2014].
Membrane proteins
Membrane proteins carry out many functions which depend on a healthy and balanced lipid bilayer structure. As mentioned above, the types of lipids vary from one membrane to another, and the proteins found on different cells or organelles vary even more widely, depending on the cell’s function. The most common membrane proteins include [Tartora and Grabowski, 2000]:
Receptors: These bind to specific molecules, called ligands, which affects a particular cellular function. For example, when hormones bind to their specific receptor, this leads to conformational changes of the receptor protein. This, in turn, triggers a reaction on the inside of the cell, which can lead to the activation or inactivation of particular genes being expressed, or trigger other reactions. As this process directs the destiny and function of the cell, the correct conformation and distribution of receptor proteins are crucial for correct cell function. And whilst our chromosomes contain the genes that code for our phenotype, i.e. the proteins that make up our bodies, it is such signals that determine which genes are being expressed and when. The exciting field of epigenetics looks into these interactions between our environment (internal and external) and our genes.
Channels and transporters: Whilst the lipid bilayer acts as a barrier, exchange between the inside and outside of the cell or an organelle is, of course, essential, for example, to let nutrients in and waste matter out. This exchange happens through channel and transporter proteins.
Channels are pores which are usually selective for particular substances such as sodium or potassium ions and can be opened or closed through either the binding of a ligand or a change in the transmembrane voltage. Ion channels are essential for transmembrane potentials which regulate many other processes. Transporters on the other hand bind to a substance on one side of the membrane and through a conformational change transport it to the other side where it can be released.
Cell membranes are permeable to water, and ion channels and transporters are involved in cell hydration, which appears to play an important role in regulating cell function [Häussinger D, 1996].
Other membrane proteins include enzymes and cell identity markers which for example help cell-cell recognition as well as recognition and distinction between self and foreign cells.
Mitochondria
Mitochondrial dysfunction has been recognised as an important cause of ill health and is implicated in ageing and many chronic conditions, including cancer, metabolic disease like diabetes, inflammatory conditions and neurodegenerative diseases such as Alzheimer’s and Parkinson’s [Coppotelli and Ross, 2016]. This should come as no surprise, being the powerhouses of the cell, they produce cellular energy without which no cell can function.
Mitochondria are complex membrane structures whereby the outer lipid layer is smooth, whilst the inner layer is highly folded to increase surface area. This is where aerobic cellular energy production through the electron transport chain takes place, producing ATP (adenosine triphosphate) the energy currency of the cell. More than 80% of cellular energy is produced here [Papa, 1996].
The inner cavity, or matrix, of the mitochondria, contains mitochondrial ribosomes (which synthesize proteins), RNA and DNA, as well as large numbers of enzymes, including some for the production proteins and lipids. Apart from energy production, mitochondria also play a crucial role in other cellular functions including:
- Modulation of calcium signaling.
- Maintenance of cellular redox balance.
- Innate immune signaling.
- Regulation of apoptosis (programmed cell death). [Bohovych and Khalimonchuk, 2016]
Apoptosis is an important process in an organism’s lifecycle and can be triggered by internal stress signals or external signals from other cells. Dysregulation of apoptosis can lead to serious disease.
For example, too little cell death can lead to the proliferation seen in cancer, whereas increased apoptosis can cause tissue damage and is implicated in neurodegenerative disease [Kaczanowski, 2016].
Cholesterol
Cholesterol is a lipid molecule which is essential for all animals and can be synthesised by all animal cells. Humans produce about 1g of cholesterol a day and about 80% of it is manufactured in the liver. We can also get small amounts of cholesterol from our food. Cholesterol is broken down to bile acids in the liver and excreted with the bile which we need for fat digestion (see “liver module”). About 95% of excreted bile acids are reabsorbed via the enterohepatic circulation and reused [Wolkoff and Cohen, 2003].
As we have seen in “cell membranes”, cholesterol is an essential component of cell membranes in animals and affects membrane fluidity as well as function, such as cell signalling, intracellular transport and nerve conduction [Yeagle PL, 1991]. Cholesterol is also the precursor for vitamin D and steroid hormones, including cortisol, aldosterone and sex hormones.
High cholesterol levels are considered to be a risk factor for cardiovascular disease, especially when in combination with other risk factors, such as smoking, hypertension, lack of exercise and other abnormal blood markers as seen in metabolic syndrome. Conventional medicine has therefore focussed on lowering blood cholesterol levels, and whilst there is an upper normal limit, there is no lower normal limit set. Too little cholesterol, however, has been associated with depression and suicide [Partonen et al, 1999], cancer [Schatzkin, 1988] and haemorrhagic stroke [Iribarren et al, 1996]. On the cellular membrane level in terms of membrane fluidity and function, as well as on the epidemiological level, it’s all in the balance, neither too much nor too little cholesterol is conducive to good health.
Medications to reduce cholesterol levels, such as statins, work by suppressing cholesterol synthesis in the liver. Unfortunately, that also affects synthesis of coenzyme Q10 (also called ubiquinone), a crucial antioxidant, in particular for cell membranes, which is clearly not desirable. Statins can also have potentially serious side effects including peripheral neuropathy, hepatitis, pancreatitis, memory loss, muscle inflammation, elevation of blood glucose levels and increased risk of diabetes [NHS 2018]. Lifestyle interventions for elevated cholesterol include diet (e.g. increasing fibre and omega 3 essential fats from oily fish), exercise and smoking cessation, which of course offer many other benefits, too. Administration of plant sterols has also been shown to help reduce elevated cholesterol levels.
Plant sterols
Plant sterols, also called phytosterols, have a similar structure to cholesterol and have similar functions in plant cells. There are over 200 types of phytosterols and related compounds (like stanols), with beta-sitosterol being one of the most abundant ones. A typical Western diet delivers about 200-300mg of sterols per day, but this can be up to 700mg per day in specifically designed vegetarian diets [Jesch and Can, 2017].
Plant sterols and LDL cholesterol
Intakes of 1-3g of phytosterols per day have repeatedly been shown to lower cholesterol levels, or more specifically, LDL (“bad”) cholesterol. It is thought that they do so by blocking cholesterol absorption [AbuMweis, 2008].
As such levels of intake of phytosterols are unlikely to be achieved by diet alone and with the importance that has been put onto lowering cholesterol in public health, phytosterols have become a popular functional food ingredient. Unfortunately, many of these functional foods, like margarines and yoghurt drinks, also contain many ingredients that, from a naturopathic nutrition perspective, we want to avoid: like highly processed vegetable oils, sugars and fillers. Dietary supplements without any artificial ingredients offer a valuable alternative.
Prostate health
Apart from their benefits on cholesterol levels, phytosterols have also shown benefits in other areas of health, including prostate health. A number of clinical trials showed clinical improvements in benign prostate hyperplasia (BPH) with administration of beta-sistosterol [Klippel et al, 1997; Wilt et al, 1999; Berges et al, 2000]. The mechanism for the efficacy of beta-sistosterol is unknown but may be due to its effect on either cholesterol metabolism or anti-inflammatory effects via prostaglandin metabolism [Wilt et al, 1999].
Other possible health benefits
Phytosterols are thought to have anti-inflammatory and immune modulatory effects [Bouic and Lamprecht, 1999], although more research is needed to establish how and to what extent plant sterols modulate inflammatory and other immune processes [Othman et al, 2011].
Preclinical studies have also shown that phytosterols may possess anti-cancer properties by inhibiting growth and inducing apoptosis in tumour cells [Awad AB, 1998; Von Holtz et al, 1998; Awad et al, 2000]. We know of course that diets high in vegetables and other plant foods, which would contain phytosterols, appear to have a cancer-protective effect but more research is needed to confirm such benefits of plant sterols.
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