Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications

Abstract

Obesity is associated with an increased risk of nonalcoholic fatty liver disease (NAFLD). Steatosis, the hallmark feature of NAFLD, occurs when the rate of hepatic fatty acid uptake from plasma and de novo fatty acid synthesis is greater than the rate of fatty acid oxidation and export (as triglyceride within very low-density lipoprotein). Therefore, an excessive amount of intrahepatic triglyceride (IHTG) represents an imbalance between complex interactions of metabolic events. The presence of steatosis is associated with a constellation of adverse alterations in glucose, fatty acid, and lipoprotein metabolism. It is likely that abnormalities in fatty acid metabolism, in conjunction with adipose tissue, hepatic, and systemic inflammation, are key factors involved in the development of insulin resistance, dyslipidemia, and other cardiometabolic risk factors associated with NAFLD. However, it is not clear whether NAFLD causes metabolic dysfunction or whether metabolic dysfunction is responsible for IHTG accumulation, or possibly both. Understanding the precise factors involved in the pathogenesis and pathophysiology of NAFLD will provide important insights into the mechanisms responsible for the cardiometabolic complications of obesity.

Figures

Figure 1

Physiological interrelationships among fatty acid metabolism, insulin resistance, dyslipidemia, and intrahepatic triglyceride content in nonalcoholic fatty liver disease (NAFLD). The rate of release of FFA from adipose tissue and delivery to the liver and skeletal muscle is increased in obese persons with NAFLD, which results in an increase in hepatic and muscle FFA uptake. In addition, intrahepatic de novo lipogenesis (DNL) of fatty acids is greater in subjects with NAFLD than in those with normal intrahepatic triglyceride (IHTG), which further contributes to the accumulation of intracellular fatty acids. The production and secretion of TG in VLDL is increased in subjects with NAFLD, which provides a mechanism for removing IHTG; however, the rate of secretion does not adequately compensate for the rate of TG production. Increased plasma glucose and insulin associated with NAFLD stimulate DNL and inhibit fatty acid oxidation, by affecting sterol regulatory element binding protein (SREBP-1c) and carbohydrate responsive element binding protein (ChREBP). These metabolic processes lead to an increase in intracellular fatty acids that are not oxidized or exported within VLDL-TG, and are esterified to TG and stored within lipid droplets. Certain lipid intermediates of fatty acid metabolism can impair insulin signaling and cause tissue insulin resistance. Therefore, this scheme illustrates how alterations in fatty acid metabolism can lead to an accumulation of intrahepatic (and intramuscular) TG, stimulate VLDL-TG secretion with subsequent hypertriglyceridemia, and cause insulin resistance in the liver and skeletal muscle.

Figure 2

Alterations in cellular fatty acid transport facilitate ectopic fat accumulation in the liver and skeletal muscle. The fatty acid translocase, CD36, regulates tissue FFA uptake from plasma. CD36 expression and protein content is decreased in adipose tissue, but increased in the liver and skeletal muscle of insulin-resistant animals and human subjects who have increased intrahepatic and intramyocellular triglyceride content. These findings suggest that alterations in tissue fatty acid transport could be involved in the pathogenesis of ectopic triglyceride accumulation by redirecting plasma fatty acid uptake from adipose tissue toward other tissues.

Figure 3

Total VLDL-TG secretion rate (sum of grey and white bars) in subjects with normal and increased (nonalcoholic fatty liver disease [NAFLD]) intrahepatic triglyceride (IHTG) content, who were matched on BMI and percent body fat. White bars represent fatty acids in VLDL-TG that originated from systemic plasma free fatty acids, presumably derived primarily from lipolysis of subcutaneous fat, whereas black bars represent fatty acids in VLDL-TG that originated from non-systemic fatty acids, presumably derived primarily from lipolysis of intrahepatic and visceral fat and de novo lipogenesis. *Value significantly different from corresponding value in the Normal IHTG group, P < 0.05. (Adapted from: Fabbrini E, Mohammed BS, Magkos F, Korenblat KM, Patterson BW, Klein S. Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease. Gastroenterology 2008;134:424–431).

Figure 4

Relationship between VLDL-TG secretion rate and intrahepatic triglyceride content (IHTG) in subjects with normal IHTG (triglyceride content 10% of liver volume). (Adapted from: Fabbrini E, Mohammed BS, Magkos F, Korenblat KM, Patterson BW, Klein S. Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease. Gastroenterology 2008;134:424–431).

Figure 5

Relationship between intrahepatic triglyceride (IHTG) content and skeletal muscle insulin sensitivity, defined as the percent increase in the rate of glucose disposal in response to insulin infusion during a hyperinsulinemic-euglycemic clamp procedure. (Adapted from: Korenblat KM, Fabbrini E, Mohammed BS, Klein S. Liver, Muscle, and Adipose Tissue Insulin Action Is Directly Related to Intrahepatic Triglyceride Content in Obese Subjects. Gastroenterology 2008).

Figure 6

Potential cellular mechanisms responsible for the relationship between fatty acid metabolism and insulin resistance in the liver and skeletal muscle. Obese persons with nonalcoholic fatty liver disease have increased rates of adipose tissue lipolysis and fatty acid (FA) release into plasma and increased intrahepatic and intramyocellular triglyceride (TG) content. Intracellular FA delivered from plasma or derived from lipolysis of intracellular triglyceride (TG) can be transported to the mitochondria for oxidation, esterified to TG or partially metabolized to several lipid intermediates, long chain fatty acyl-CoA, ceramide, lysophosphatidic acid (LPA), and phosphatidic acid (PA), and diacylglycerol (DAG). These lipid intermediates can interfere with insulin signaling by activating protein kinase C (PKC), mammalian target of rapamycin (mTOR), and nuclear factor kinase B (NFκB), and inhibiting Akt (also known as protein kinase B). The oxidation of intracellular FAs involve the conversion of long-chain fatty acyl-CoAs to acylcarnitines, which enter the mitochondria, and are progressively shortened by β-oxidation, which produces acetyl-CoA that can enter the tricarboxylic acid cycle for complete oxidation. The incomplete oxidation of fatty acyl-CoA generates ketone bodies and acylcarnitines, which might also have adverse effects on insulin action. (Adapted from: Schenk S, Saberi M, Olefsky JM. Insulin sensitivity: modulation by nutrients and inflammation. J Clin Invest 2008;118:2992–3002, and Nagle CA, Klett EL, Coleman RA. Hepatic triacylglycerol accumulation and insulin resistance. J Lipid Res 2009;50 Suppl:S74–79).