Liver plays an important role in lipid metabolism. It harvests free fatty acids (FFA) from the bloodstream, stores them as lipids and exports as lipoproteins. FFAs in the liver can be metabolized either by hepatocyte mitochondria through oxidation to produce ATP or through esterification to triglycerides, which are stored as liver fat or secreted into the bloodstream as lipoprotein particles, mainly VLDL. Fatty acids can also be used for phospholipid synthesis or ketone body production. Apart from lipids, the main metabolic functions of the liver include storing glucose as glycogen, generating it by gluconeogenesis, secreting coagulation factors and producing inflammatory cytokines (369).
In a fasting state, liver releases glucose into circulation by glycogenolysis and gluconeogenesis (370). This production is enhanced by glucagon (371) and suppressed by insulin. Fatty acids from adipose tissue are oxidized in the liver mitochondria or synthesized into VLDL (372, 373). In a caloric excess state in normal healthy subjects, increasing insulin (374) and glucose concentrations suppress hepatic glucose production (375). Liver stores dietary glucose as glycogen, oxidizes it for immediate energy needs or converts the excess amounts into fat by hepatic de novo lipogenesis (376). FFAs are used to fill the hepatic triacylglycerol stores (377).
The prevalence of fatty liver increases with obesity (378, 379). Overfeeding of 4 weeks with a high- fat high-glucose diet increased weight by 9%, but liver fat content with 2-3 fold in normal healthy subjects (380). Weight loss in turn decreases liver fat content (381). The relationship of body weight and the accumulation of liver fat however is not linear (382). Some subjects develop fatty liver at different obesity stages than others. In accordance with this, metabolically healthier insulin sensitive obese subjects have been suggested to have less liver fat than their insulin resistant peers (16, 382). A study on monozygotic twins discordant for obesity has shown that liver fat content is increased in acquired obesity independent of genetic effects (383). However, it is not known, if liver fat or some other metabolic measure distinguishes between health and disease in obesity, and if this association is genetic or acquired.
Figure 8: Liver fat accumulation
Figure 8: Obesity and excess energy intake cause adipocyte hypertrophy and adipose tissue enlargement. Excess subcutaneous adipose tissue enlargement stresses the tissue, causing mitochondrial dysfunction, increased lipolysis, increased inflammatory secretion, altered adipokine secretion and insulin resistance of the tissue. Inability of the subcutaneous fat to enlarge sufficiently leads to increased FFA concentrations in the circulation which deposit as ectopic fat in the liver. Inflammatory cytokines secreted by adipocytes and adipose tissue inflammatory cells together with the increased fat content contribute to the insulin resistance state of the liver and the whole body. Increased liver fat accumulation, whole-body inflammation and insulin resistance present as metabolic syndrome.
Non-alcoholic fatty liver disease (NAFLD) is defined as a state where over 5% of liver content or weight is fat. Insulin resistance and inflammatory state, caused by obesity and excess triglycerides, in adipose and other peripheral tissues such as muscle, also contribute to the increase in plasma glucose and inflammatory secretion to the circulation. These factors in turn contribute to the fatty acid deposition and development of inflammation and insulin resistance in the liver. In the insulin resistant, fatty liver, glucose production is not inhibited despite the increased blood glucose concentrations. Liver produces excess VLDL particles contributing to the hypertriglyceridemia often seen in obesity, hyperglycemia by glucose production, systemic inflammation by inflammatory molecule expression and secretion and increased probability of thrombosis by increased thrombotic factor secretion. Endoplasmic reticulum (ER) stress in adipose tissue and factors secreted by gut microbiota may contribute to the FFA deposition and insulin resistance of the liver.
In obesity, continuous accumulation of fatty acids in liver and inflammatory factors secreted by adipose tissue (384, 385) can lead to a non-alcoholic fatty liver disease (NAFLD). This comprises a spectrum of disorders from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH) and on to fibrosis and cirrhosis (386). NAFLD is defined as more than 5% fat content of liver volume or liver weight (387) and histologically when 5% or more of the hepatocytes contain intracellular visible triglycerides (388). Features of steatohepatitis include hepatocellular injury (ballooning, apoptosis and necrosis, Mallory's hyaline bodies and giant mitochondria in hepatocytes), inflammatory milieu and fibrosis (389). Many (390, 391) studies have found that VLDL-particle secretion from liver is greater in patients with NAFLD than in those with normal hepatic triglyceride concentrations. However, for some reason the increased secretion is not enough to compensate for the increased liver fat deposition.
Intra-hepatic triglyceride content has been directly linked to hepatic insulin resistance by many studies (326, 392, 393) and NAFLD associated with insulin resistance (394, 395) and obesity (392, 395). The relationship of fatty liver and insulin resistance has been suggested to be independent of total body fat, visceral fat (396) and intramyocellular fat (397). The development of insulin resistance and inflammation in the liver is thought to happen simultaneously, at the same time during the increase in liver fat content. Visceral and subcutaneous adipose tissue enlargement produces both excess FFAs and inflammatory factors, which activate cascades to impair insulin signaling in the liver (384). FFAs are released and deposited ectopically uninhibited because of the insulin resistant state in the adipose depots (398). Adipose tissue derived inflammatory factors and impaired liver function in turn has been evidenced by an increased expression of inflammatory markers in subcutaneous adipose tissue of obese women with high liver fat content compared with obese women with normal amounts of liver fat (399). Insulin resistant state in the liver and other tissues enhance pancreatic β-cell insulin secretion, and NAFLD has been associated with pancreatic β-cell exhaustion and dysfunction in obese subjects (400, 401).
In the fatty, insulin-resistant liver the insulin clearance from bloodstream is reduced (402). Inhibition of hepatic glucose production becomes impaired (326) and the secretion of VLDL lipoprotein particles is not sufficiently inhibited (391). Liver overproduces both glucose and VLDL, and plasma glucose and lipoprotein levels rise. Cytokines and coagulation factors are overproduced. The results of fatty liver - hyperglycemia, hypertriglyceridemia, low HDL cholesterol concentration and hyperinsulinemia - are commonly, but not always, seen in the obese state. Hepatic triglyceride accumulation does not necessarily cause insulin resistance, as demonstrated by mouse studies (403, 404). Thus, while those obese that accumulate ectopic fat and have hypertriglyceridemia and hyperglycemia are known to be at risk for cardiovascular disease and other metabolic complications of obesity (405), recent discussion has focused on the possibility that liver fat accumulation might distinguish between the obese developing metabolic complications from those who do not.