Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are becoming an increasing burden in the western world, with about 10% - 24% of the population worldwide affected [[i]], [[ii]].The common feature of NASH and NAFLD is the accumulation of fat, mainly triglycerides, in the liver. The presence of triglyceride droplets in >5% of hepatocytes accumulated by consumption of less than 20 g alcohol/day defines NAFLD.
Figure 1: Histological staining of lipid droplets in a mouse liver with Fatty Liver Disease (right picture) and a normal healthy liver (left). Lipid droplets are seen as white huge bubbles which are basically not present in the healthy liver. Primarily, NAFLD is considered to be the hepatic manifestation of the metabolic syndrome [[i]], [[ii]] which is defined by the World Health Organization (WHO) as a medical disorder when the following criteria are set: impaired glucose tolerance, impaired fasting glucose or insulin resistance, and two of the following: high blood pressure, dyslipidemia and central obesity caused by excessive lipid deposition in adipose tissue as well as ectopically in pancreas, muscle and liver [[iii]]. Ectopic lipid accumulation interferes with intracellular insulin signalling cascades and thus directly induces insulin resistance. Insulin resistance particularly contributes to the imbalance between lipid availability and lipid disposal in the liver. Apart from obesity caused by nutrient overconsumption especially of fats and sugar, also malnutrition, including fast weight loss, drugs, toxins or infections, which are considered secondary causes of non-alcoholic fatty liver disease, can lead to NAFLD [[iv]]. While NAFLD often goes without symptoms, it can worsen and develop into NASH which is accompanied by inflammation and liver damage which can eventually lead to liver cirrhosis and even to liver cancer [[v]]. Cardiovascular and coronary artery disease are the major cause of death in patients with non-alcoholic fatty liver disease (NAFLD) due to perturbed lipoprotein metabolism leading to proatherogenic dyslipidemia [[i]]. This involves increased lipolysis and VLDL secretion leading to hypertriglyceridemia, increased release of inflammatory factors such as C-reactive protein from the liver, hyperglycemia and hypercholesterolemia including decreased HDL [rev. in [[ii]]. These conditions can lead to heart failure, diabetis mellitus type II and/or stroke [[iii]], [[iv]].
Figure 2: Triglycerides (TG) are normally stored in adipose tissue and if required transported to the liver as free fatty acids (FFA) where they are taken up and re-processed into triglycerides, or used for the production of hormones, cholesterol or other molecules. Triglycerides which were taken up with the diet are immediately transported to the liver to be processed. Yet, the liver has only a limited capacity to metabolize triglycerides. If the blood triglycerides are already elevated the liver has to handle elevated triglyceride levels by storing them temporarily. If this condition continues and fats are not transported out of the liver, NAFLD will develop which eventually might progress to NASH. The liver is the central organ of metabolism of carbohydrates and lipids, including cholesterol, fatty acid and triglyceride metabolism, orchestrating lipid metabolism for the whole body. Normally, triglycerides are stored in adipose tissue and if required are transported to the liver as fatty acids where they are taken up and processed into triglycerides, hormones, cholesterol or other molecules. Excessive fat accumulation in the adipose tissue leads to the constant secretion of free fatty acids along with pro-inflammatory so-called adipokines, a special kind of cytokines which are secreted from fat cells. This will then lead to ectopic fat accumulation in the pancreas, skeletal muscle and in the liver resulting in whole body insulin resistance. This, along with additional triglycerides available through diet, which are immediately transported to the liver, results in an overload of fats, which will end up in hepatic steatosis. Insulin increases the lipolysis of peripheral adipose tissue. Additionally, insulin triggers de novo triglyceride synthesis within the liver and inhibits fatty acid oxidation which results in further triglyceride accumulation in the hepatocytes [[i]], [[ii]]. [i] Musso G, Gambino R, Cassader M. Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD). Prog Lipid Res. 2009 Jan;48(1):1-26 [ii] Wu X, Chen K, Williams KJ. The role of pathway-selective insulin resistance and responsiveness in diabetic dyslipoproteinemia. Curr Opin Lipidol. 2012 Aug;23(4):334-44 [i] Chatrath H, Vuppalanchi R, Chalasani N.Semin Dyslipidemia in patients with nonalcoholic fatty liver disease. Liver Dis. 2012 Feb;32(1):22-9 [ii] Gaggini M, Morelli M, Buzzigoli E, DeFronzo RA, Bugianesi E, Gastaldelli A. Non-alcoholic fatty liver disease (NAFLD) and its connection with insulin resistance, dyslipidemia, atherosclerosis and coronary heart disease. Nutrients. 2013 May 10;5(5):1544-60 [iii] Wang Y, Li YY, Nie YQ, Zhou YJ, Cao CY, Xu L Association between metabolic syndrome and the development of non-alcoholic fatty liver disease. Exp Ther Med. 2013 Jul;6(1):77-84 [iv] Tarantino G, Finelli C. What about non-alcoholic fatty liver disease as a new criterion to define metabolic syndrome? World J Gastroenterol. 2013 Jun 14;19(22):3375-84 [i] Vanni E, Bugianesi E, Kotronen A, De Minicis S, Yki-Järvinen H, Svegliati-Baroni G. From the metabolic syndrome to NAFLD or vice versa? Dig Liver Dis. 2010 May;42(5):320-30 [ii] Gastaldelli A. Fatty liver disease: the hepatic manifestation of metabolic syndrome. Hypertens Res. 2010 Jun;33(6):546-7 [iii] Hamaguchi M, Takeda N, Kojima T, Ohbora A, Kato T, Sarui H, Fukui M, Nagata C, Takeda J. Identification of individuals with non-alcoholic fatty liver disease by the diagnostic criteria for the metabolic syndrome. World J Gastroenterol. 2012 Apr 7;18(13):1508-16 [iv] Adams LA, Angulo P Treatment of non-alcoholic fatty liver disease Postgrad Med J. 2006 May;82(967):315-22 [v] Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: old questions and new insights. Science. 2011 Jun 24;332(6037):1519-23 [i] Vernon G, Baranova A, Younossi ZM Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011 Aug;34(3):274-85 [ii] Hamaguchi M, Takeda N, Kojima T, Ohbora A, Kato T, Sarui H, Fukui M, Nagata C, Takeda J. Identification of individuals with non-alcoholic fatty liver disease by the diagnostic criteria for the metabolic syndrome. World J Gastroenterol. 2012 Apr 7;18(13):1508-16
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