Familial hypercholesterolemia (FH) is a monogenic genetic disorder that affects in its heterozygous form 1:500 of the population. It is associated with mutations in low-density lipoprotein receptor (LDLR), apolipoprotein B and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. PCSK9 normally directs lysosomal degradation of LDLR and has been proposed as an attractive target of cholesterol-lowering therapy. In a paper published in Hepatology, Zaid and colleagues analyze the liver-specific role of PCSK9 and reveal its crucial part in liver regeneration. They show that the liver is the major site of expression and source of circulating PCSK9; still extra-hepatic tissues depend on their own expression to regulate LDLR activity. PCSK9 deficiency is also associated with retarded hepatic recovery after partial hepatectomy.
PCSK9 belongs to a family of enzymes responsible for the tissue-specific processing of various precursor proteins including growth factors and neuropeptides. Unlike the other members of the family, it is only involved in its autocatalytic processing and has no other known substrates. By binding on the EGF-A domain of the LDLR, it acts as a chaperone and targets the receptor for degradation [1]. According to previous studies, gain- and loss-of-function mutations in PCSK9 can cause hypercholesterolemia and hypocholesterolemia respectively [2]. Zaid et al. show that PCSK9 is primarily expressed in the liver, within which hepatocytes are the only cell population responsible for its synthesis. Using Cre/loxP recombination they created total (-/-) and hepatocyte-specific (f/f Alb-Cre, Cre under the control of the albumin promoter) knockouts, which allow a closer look at the liver-specific role of PCSK9. This rev...
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... of parabiotic mice, J Clin Invest 116 (2006), no. 11, 2995-3005.
4. J. M. Dietschy, S. D. Turley and D. K. Spady, Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans, J Lipid Res 34 (1993), no. 10, 1637-1659.
5. N. G. Seidah, S. Benjannet, L. Wickham, J. Marcinkiewicz, S. B. Jasmin, S. Stifani, A. Basak, A. Prat and M. Chretien, The secretory proprotein convertase neural apoptosis-regulated convertase 1 (narc-1): Liver regeneration and neuronal differentiation, Proc Natl Acad Sci U S A 100 (2003), no. 3, 928-933.
6. N. Gupta, N. Fisker, M. C. Asselin, M. Lindholm, C. Rosenbohm, H. Orum, J. Elmen, N. G. Seidah and E. M. Straarup, A locked nucleic acid antisense oligonucleotide (lna) silences pcsk9 and enhances ldlr expression in vitro and in vivo, PLoS One 5 (2010), no. 5, e10682.
This case study is about Abdul Chidiac, a 51 year old male, married with 4 children. He had a medical history of hypertension, hypercholesterolaemia and cirrhosis with two admissions in the last six months. He is a smoker and drinks beer, 5-6 bottles per day. As Carithers & McClain (2010) explained the patient’s medical history is another indicator of the risk for cirrhosis; the progression to cirrhosis is adaptable and may take time over weeks or many years. Cirrhosis is a liver disease characterized by permanent scarring of the liver that interferes with its normal functions including alcoholism. Most people who drink large amounts of alcohol cause harm to the liver in some way (Heidelbaugh & Bruderly, 2006). The cause of cirrhosis is not yet known, but the connection between cirrhosis and excessive alcohol ingestion is established (Jenkins & Johnson, 2010). Common causes of cirrhosis include: alcohol abuse, hepatitis B infection, hepatitis C infection and non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (Schuppan & Afdhal, 2008).
In normal individuals, the capacity of the liver to phosphorylate fructose (fructokinase activity) greatly exceeds the liver's capacity to split fructose 1-phosphate (aldolase B activity). Why is a deficiency of fructokinase a less serious genetic defect than a deficiency of fructose 1-phosphate aldolase? Consider what happens to fructose in each case and what effect this has on hepatic metabolism. (20
The gut microbiota obtains its nutrients from various sources such as consumed dietary ingredients and host-derived requirements like epithelial cells and mucus. Microorganisms utilize these substrates to produce energy to modulate cellular processes, metabolism and growth. The gut encompasses pathways for carbohydrate, lipid and amino acid metabolism (6). Interestingly, the gut flora’s metabolic action is both adaptive and renewable. Through the synthesis of short-chain fatty acids (SCFAs), B vitamins and vitamin K, commensal bacteria mutualistically interact with intestinal epithelial cells to promote differentiation, proliferation and absorption from the bowel. Jointly, this metabolic mechanism preserves valuable energy and digestible substrates for the host, all while supplying energy and nutrients for growth (9). SCFAs (mainly acetate, butyrate and propionate) are the final products of the carbohydrate fermentation of dietary fibers, and exhibit many positive influences in countering metabolic and inflammatory disorders, for instance, obesity, diabetes, and inflammatory bowel disease. This is accomplished via the activation of G-protein-coupled receptors and alteration of transcription factors (17, 18). The microbial assembly of SCFAs, TMA, acetaldehyde and inflammatory regulators control the metabolic fitness of the host through pathways that affect gut motility, immune function and satiety (19). An example of a lipid metabolic activity that relates the gut flora to dyslipidemia (excessive amount of lipids) is the hydrolysation of bile salts, which are steroid acids manufactured in the liver from cholesterol and secreted in bile to accelerate absorption of fat-soluble vitamins, along with the metabol...
Hypercholesterolemia is the presence of high levels of cholesterol in the blood. Cholesterol is a waxy fat-like substance and is a major class of lipid, so it gets into the blood by lipoproteins [1]. A high level of lipoproteins is unhealthy. A high level can result in an elevated risk of atherosclerosis and coronary heart disease [2]. The high levels of lipoproteins are often influenced by a combination of genetic and environmental factors such as obesity or dieting habits [2]. High cholesterol can be caused by mutations in the following genes: APOB, LDLR, LDLRAP1, and PCSK9 [3]. Mutations in the LDLR gene are responsible for causing familial hypercholesterolemia, which is the most commonly seen form of inherited high cholesterol [3]. The LDLR gene contains instructions for making LDL receptors or low-density lipoprotein receptors. LDL receptors play critical roles in regulating levels of cholesterol in the blood by removing low-density lipoproteins from the bloodstream. Mutations in the LDLR gene can make the amount of LDL receptors produced less than normal or affect their job of removing the low-density lipoproteins in the blood [4]. People who have these mutations will have higher levels of cholesterol. There are many ways that the environment can affect the levels of cholesterol in the blood. Reducing the amount of dietary fat you consume lowers the total amount of cholesterol in the blood [5]. Sucrose and fructose can raise the amount of LDL in the blood. Reducing fatty foods will however lower the amount of LDL [5]. Having a healthy body and maintaining physical exercise plays a key role in keeping your cholesterol at a healthy level. If you are overweight or obese you can lower your cholesterol levels by simply losing ...
Nikitina, E. G., Urazova, L. N., & Stegny, V. N. (2012). MicroRNAs and Human Cancer.Experimental Oncology, 34(1), 2-8. Retrieved from http://archive.nbuv.gov.ua/portal/chem_biol/eol/2012_1/002.pdf
Liver disease resulting from alcohol affects more than two million Americans and is one of the primary causes of illness and death. The liver frees the body of harmful substances, such as alcohol. While the liver breaks down alcohol, it produces toxins that can be even more dangerous than the alcohol consumed (“Beyond Hangovers: Understanding Alcohol's Impact Your Health” 13). “These by-products damage liver cells, promote inflammation, and weaken the body’s natural defenses. Eventually, these problems can disrupt the body’s metabolism and impair the function of other organs” (“Beyond Hangovers: Understanding Alcohol's Impact Your Health” 13). A condition called steatosis is the result of fat build up in the liver and is the earliest stage of alcoholic liver disease. This condition causes the liver difficulty breaking down alcohol, potentially resulting in alcoholic hepatitis. Fibrosis of the liver, which is also related to heavy drinking, causes scar tissue to build up in the liver. The alcohol alters chemicals that the liver needs to break down this scar tissue, causing liver dysfunctions. If one does not refrain from drinking during the condition of fibrosis, the scar tissue can build up and create another condition, called cirrhosis. Cirrhosis is deterioration of the liver resulting from heavy scarring, causing the liver to not be able to function properly. If cirrhosis becomes severe, a liver transplant may be the only solution (“Beyond Hangovers: Understanding Alcohol's Impact Your Health” 14). It is difficult to calculate when a person would develop cirrhosis, because an alcoholic could never develop the disease, but someone who social drinks could. It is also unknown why cirrhosis is more prevalent in women (...
Figure 2 Cirrhosis of the liver in relation to alcohol consumption. (Publication in Parliament 2010)
Liu, L.Y., Alexa, K., Cortes, M., Schatzman-Bone, S., Kim, A.J., Mukhopadhyay, B., Cinar, R., Kunos, G., North, T.E. & Goessling, W. (2016). Cannabinoid receptor signaling regulates liver development and metabolism. Development, 143:
Kwiterovich, P, O.(Ed). (2010). The Johns Hopkins Textbook of Dyslipidemia. USA: Lippincott Williams & Wilkins.
There are many risk factors which can lead to the development of atherosclerosis. As can be expected, one of the risks factors for atherosclerosis is related to the abnormal level of blood lipids. The role of abnormal blood lipids in the development of atherosclerosis is providing the boost required for lipid to be transported to cells, as well as the production of reactive oxygen and free radicals (p.700). Moreover, the quantity of cholesterol carried by low-density lipoproteins (LDLs) in the arterial wall is critical in the development of atherosclerosis (McCance
Like many of the organs in our body, the liver plays a vital role and function in our body, which in turn helps keep our bodies nice and healthy. The liver is the second largest organ in our body, located just underneath the rib cage on the right side. Some of the liver’s functions include: producing bile, producing proteins, metabolizing nutrients, removing potentially toxic byproducts of certain medications, and helping our body fight infection by removing bacteria from the blood. Although the liver can carry out its necessary functions in its healthy state, there is a disease which causes damage to the liver called, liver cirrhosis. It is important to learn and educate ourselves on the many aspects
Liver is the principal site for protein metabolism. Although the liver plays a vital role in carbohydrate and fat metabolism, its function in protein metabolism is of critical importance, as the failure to do so for more than a few days can result in death. This includes deamination and transamination of amino acids, urea formation to remove ammonia from body fluids, formation of approximately 90% of all plasma proteins, and synthesis of non-essential amino acids (Donohue Jr, 1996).
Tortora & Derrickson (2009) further illuminates the distinction between LDL and HDL cholesterols and why these differences incur such conflicting effects in the body. LDLs convey about 75% of the total cholesterol in blood and deliver it throughout the body to cells so that they may repair cell membranes and create steroid hormones and bile salts (p. 991). However, when their number exceeds what is necessary, LDLs leave cholesterol in and around the smooth muscle fibers in arteries (p. 991). Thus, LDLs have earned a “bad” reputation. In contrast, HDLs remove excess cholesterol from body cells and blood and transport it to the liver for subsequent elimination, preventing its accumulation in the blood (p. 991). Thus, their “good” reputation is safe. It is important to remember though that both LDL and HDL cholesterols, as well as triglycerides, are essential in certain amounts, and LDLs and HDLs together make up the total cholesterol level used in the diagnosis of high cholesterol.
A number of organs have the intrinsic ability to regenerate, a distinctive feature that varies among organisms. Organ regeneration is a process not fully yet understood however when its underlyning mechanism are unreveled, it holds tremendous therapeutic potential for humans. [28]