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International Chair on Cardiometabolic Risk
My Healthy Waist

Liver Fat

Defining CMR - Visceral Adipose Tissue: the Culprit? A Marker of Ectopic Fat Deposition?

Key Points

  • Non-alcoholic fatty liver disease is a common cause of chronic liver disease and is closely associated with a range of cardiometabolic risk factors as well as diabetes and mortality risk.
  • It is unknown how liver fat develops but a number of plausible mechanisms have been proposed, including “spillover” of excess energy from adipose tissue, adiponectin deficiency, a high fat diet, and/or overactivation of the endocannabinoid system.
  • Increased liver fat storage is related to hepatic insulin resistance and increased synthesis and secretion of atherogenic lipoproteins.
  • The gold standard method for quantifying liver fat is liver biopsy.
  • However, imaging techniques such as magnetic resonance spectroscopy (MRS) and computed tomography (CT) are safe and reliable alternatives.

Liver Fat: a Marker of Ectopic Fat Deposition

The term ectopic comes from the Greek word ektopos, meaning “out of place.” It has been used to denote fat storage in non-adipose tissue, such as the liver, muscle, pancreas, heart, and others [1]. Recent findings have demonstrated that fat storage in non-adipose tissue causes many of the metabolic complications of obesity [1-3]. Fat storage in the liver is particularly associated with a range of metabolic complications [4-15].

Fatty liver is a key component of non-alcoholic fatty liver disease, a broad condition first described by Leevy et al. [16] in 1962. This disease has symptoms similar to that of alcohol-induced liver damage but is found in non-alcohol abusers. Symptoms are wide-ranging and include fatty infiltration of the liver (hepatic steatosis), fatty infiltration and liver inflammation (non-alcoholic steatohepatitis), and fibrosis and cirrhosis, which can ultimately lead to liver failure.

Non-alcoholic fatty liver disease has emerged as one of the most widespread causes of chronic liver disease [17]. Because of its ability to predict type 2 diabetes risk [18] and its association with various metabolic disturbances [4-15], non-alcoholic fatty liver disease has been proposed as a new potential component of the metabolic syndrome [7].

Epidemiology

Based on increased serum liver enzyme levels, estimates from the third National Health and Nutrition Examination Survey suggest that 6.4 million adults in the United States have non-alcoholic fatty liver disease [19]. As assessed using specialized imaging techniques such as magnetic resonance imaging, fatty liver is found in about 30% of all adults in the United States [20,21]). Non-alcoholic fatty liver disease is much more common in older individuals, with over 30% of adults afflicted [20,21] compared to less than 3% of children [22]. Disease prevalence also varies by sex and is higher among males than females [19,20]. It also varies by race, being highest among Hispanics (45%), followed by Whites (33%), and Blacks (24%) [20]. Roughly half of all diabetics and three-quarters of obese individuals have non-alcoholic fatty liver disease [23,24]. Although liver fat is commonly associated with obesity [25-27], fatty liver can be present in non-obese subjects as well [5,7]. Risk factors for a fatty liver in normal weight individuals include dyslipidemia, insulin resistance, and abdominal obesity [28], all components of the metabolic syndrome.

Liver Fat and Metabolic Diseases

Although originally considered an inconsequential finding, fatty liver has since emerged as a predictor of type 2 diabetes [18] and a potential component of the metabolic syndrome [7]. In fact, it has been documented that non-alcoholic fatty liver disease raises mortality risk [29]. A number of studies have reported that liver fat is linked to health risk factors, including hypertension [30], insulin resistance (4-10), elevated plasma glucose [5,10,11,13,14], elevated insulin [5,8,10,12,15], elevated triglycerides [4,5,7-15], and low levels of HDL cholesterol [5,7,8,12,14]. While the relationship of liver fat to metabolic risk, insulin resistance in particular, is clear, the mechanisms underpinning this relationship are not fully understood.

Pathogenesis

The exact pathophysiology that leads to non-alcoholic fatty liver disease and its metabolic consequences has yet to be defined, although a number of plausible explanations have been proposed. Generally, it has been suggested that adipocyte resistance to the anti-lipolytic effects of insulin [31] and/or the exhaustion of adipose tissue storage capacity [2] increase lipolysis rates and free fatty acid (FFA) delivery to the liver. This “spillover” of lipids from adipose tissue to the non-adipose tissues of the liver eventually exceeds the liver’s ability to secrete fatty acids in the form of VLDL [32], causing liver fat. Excess lipid storage in lean tissues such as the liver can then lead to lipid-induced dysfunction (lipotoxicity) [33] and lipid-induced programmed cell death (lipoapoptosis) [34] (Figure 1). Increased delivery of FFA to the liver, particularly from the visceral depot, may be responsible for hepatic insulin resistance [35], triglyceride accumulation in the hepatocytes [15,36], and increased synthesis and secretion of atherogenic lipoproteins [37].

Lipodystrophy is a rare clinical condition (either acquired or congenital) characterized by selective loss of functional adipose tissue (especially subcutaneous tissue) [38]. This condition severely limits the ability of adipose tissue to store excess energy, which means excess fat is stored in the liver and muscle, leading to insulin resistance and diabetes [39]. To combat this, pharmacological interventions have used thiazolidinediones (TZD), a family of drugs that promote the development of new subcutaneous adipocytes [40] and the expansion of the subcutaneous adipose depot, to decrease liver fat storage [41] and improve insulin sensitivity [42].

Thus, lipids are released into the circulation in proportion to the size of the adipose organ, the large fat mass in obese individuals may also elevate FFA flux to non-adipose tissues in the absence of any abnormality in adipose tissue metabolism [43]. Despite the presence of “functional” adipose tissue, the large adipose tissue mass of obese patients may become insulin resistant generating large quantities of atherogenic and diabetogenic FFA.

A “two hit” model originally developed by Day and James [44] postulates that liver fat deposition because of lipid spillover from adipose tissue is only the first of two steps leading to non-alcoholic fatty liver disease. The second “hit” of the model involves either lipid peroxidation through oxidative stress and/or cytokine action [45]. The model suggests that reactive oxygen species (of yet unknown origin) can degenerate the excess lipids stored in the liver, causing both hepatic inflammation and hepatocyte damage and, eventually, death [45]. The disease may then progress from steatosis to steatohepatitis and possibly cirrhosis. It is also possible that excess liver fat storage can increase the hepatic production of bioactive molecules such as tumour necrosis factor (TNF-α), which are also capable of having a similar harmful impact on the liver [45].

A deficiency in adiponectin, another cytokine, may also play a role in the pathogenesis of liver fat [46]. Low levels of plasma adiponectin have been linked to obesity, visceral adiposity in particular [47], insulin resistance [48], and fatty liver [49,50].

Along with suppressing the production and function of TNF-α [51], adiponectin can decrease hepatic lipogenesis and increase hepatic insulin sensitivity [52,53]. Low adiponectin levels may therefore lead to liver inflammation, liver fat accumulation by reducing insulin sensitivity, and damage through TNF-α suppression. In this respect, administering adiponectin to rodents with fatty liver has been shown to resolve the condition [54].

Another possible reason for the accumulation of liver fat is high dietary consumption of saturated fats and/or carbohydrates. It has been shown that 50% of dietary fat is taken up by the liver [55], so it is not surprising that dietary fat content is related to degree of liver fat storage [56,57]. High carbohydrate intake has also been shown to play a role in liver fat content, and the restriction of dietary carbohydrate intake may reduce liver fat storage [58].

Recent evidence suggests that the endocannabinoid system, including the cannabinoid receptor CB1 and endogenous agonists such as anandamide and 2-arachidonylglycerol (2-AG), may play a role in the pathogenesis of liver fat [59,60]. It has been proposed that obesity may be associated with overactivation of the endocannabinoid system, with elevated endocannabinoids working via the hepatic CB1 receptor to stimulate hepatic lipogenesis and subsequently lead to the development of fatty liver [59,60]. More research is needed to define the role of the endocannabinoid system in the pathogenesis of fatty liver.

Figure 1:
Lipid overflow hypothesis for the pathogenesis of liver fat

Measuring Liver Fat

Liver biopsy is generally considered the gold standard for assessing hepatic steatosis [17]. However, a liver biopsy sample is a mere 1/50,000 of total organ mass [61], and because liver tissue is so heterogeneous, this small sample is likely to be a biased estimate of overall hepatic steatosis. Studies using multiple biopsy samples have shown considerable sampling variability for various hepatic histological features, including the diagnosis and staging of non-alcoholic fatty liver disease [62]. A biopsy procedure can also cause post-procedure pain, hypotension, intraperitoneal hemorrhage, bacterial infection, and a small but definite risk of mortality [63].

Advanced imaging techniques such as computed tomography (CT) and proton-magnetic resonance spectroscopy (H1-MRS) have emerged as safe, reliable, and non-invasive alternatives to liver biopsy. Liver attenuation on a CT image depends on liver density, which depends on the degree of fat infiltration: the higher the fat content, the lower the attenuation value, and the darker the CT image of the liver (Figure 2). Strong correlations have been observed between CT and histological measures of liver fat (r=-0.77) [64]. H1–MRS, an alternate imaging technique that does not use x-ray energy, also correlates well with biopsy assessments of liver fat [64-66]. Though H1–MRS produces a quantitative measure of liver fat and CT a qualitative analysis [67], these measures correlate well with each other (r>0.80) [64,65]. Unfortunately, these imaging techniques only detect liver fat when over 30% of the liver tissue is already infiltrated with fat [68]. In addition, no imaging technique is capable of differentiating between degrees of non-alcoholic liver disease, particularly between hepatic steatosis and steatohepatitis [68], a clinically relevant distinction.

Elevated levels of two serum liver enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) [19], and an AST/ALT ratio of less than 1 [69] are the common clinical criteria used to distinguish non-alcoholic fatty liver disease from alcoholic fatty liver disease. Elevated levels of these enzymes have also been tied to cardiometabolic risk factors such as abdominal obesity, elevated blood pressure, insulin resistance, and dyslipidemia [70,71] as well as risk of cardiovascular disease [72].

Liver fat deposition is associated with a number of cardiometabolic risk factors, including abdominal obesity, hypertension, insulin resistance, and dyslipidemia. A variety of methods can be used to measure liver fat, including the standard liver biopsy as well as specialized imaging techniques such as H1-MRS and CT. Many theories have been put forth to explain how fatty liver develops and how the deposition of fat in hepatic tissue increases cardiometabolic risk. The consequences of liver fat accumulation on health is an area of very active scientific research. Many studies are conducted to better understand the etiology of non-alcoholic fatty liver disease and its related cardiometabolic complications and interesting review papers have been published on the topic [73-77].

Figure 2:
Computed tomography imaging of a normal and fatty liver

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Reference 1 CLOSECLOSE

Unger RH. Minireview: weapons of lean body mass destruction: the role of ectopic lipids in the metabolic syndrome. Endocrinology 2003; 144: 5159-65.

PubMed ID: 12960011
Reference 2 CLOSECLOSE

Ravussin E and Smith SR. Increased fat intake, impaired fat oxidation, and failure of fat cell proliferation result in ectopic fat storage, insulin resistance, and type 2 diabetes mellitus. Ann N Y Acad Sci 2002; 967: 363-78.

PubMed ID: 12079864
Reference 3 CLOSECLOSE

Heilbronn L, Smith SR and Ravussin E. Failure of fat cell proliferation, mitochondrial function and fat oxidation results in ectopic fat storage, insulin resistance and type II diabetes mellitus. Int J Obes Relat Metab Disord 2004; 28 Suppl 4: S12-21.

PubMed ID: 15592481
Reference 4 CLOSECLOSE

Banerji MA, Buckley MC, Chaiken RL, et al. Liver fat, serum triglycerides and visceral adipose tissue in insulin-sensitive and insulin-resistant black men with NIDDM. Int. J. Obes. 1995; 19: 846-50.

PubMed ID: 8963350
Reference 5 CLOSECLOSE

Marchesini G, Brizi M, Morselli-Labate AM, et al. Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med 1999; 107: 450-5.

PubMed ID: 10569299
Reference 6 CLOSECLOSE

Ryysy L, Hakkinen AM, Goto T, et al. Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients. Diabetes 2000; 49: 749-58.

PubMed ID: 10905483
Reference 7 CLOSECLOSE

Marchesini G, Brizi M, Bianchi G, et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 2001; 50: 1844-50.

PubMed ID: 11473047
Reference 8 CLOSECLOSE

Tiikkainen M, Tamminen M, Hakkinen AM, et al. Liver-fat accumulation and insulin resistance in obese women with previous gestational diabetes. Obes Res 2002; 10: 859-67.

PubMed ID: 12226133
Reference 9 CLOSECLOSE

Kelley DE, McKolanis TM, Hegazi RA, et al. Fatty liver in type 2 diabetes mellitus: relation to regional adiposity, fatty acids, and insulin resistance. Am J Physiol Endocrinol Metab 2003; 285: E906-16.

PubMed ID: 12959938
Reference 10 CLOSECLOSE

Adiels M, Taskinen MR, Packard C, et al. Overproduction of large VLDL particles is driven by increased liver fat content in man. Diabetologia 2006; 49: 755-65.

PubMed ID: 16463046
Reference 11 CLOSECLOSE

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