Pathogenesis of Atherogenic Dyslipidemia

Scott M. Grundy, MD, PhD.

In This Article

Causes of Fatty Liver

If hepatic lipid overload is the major factor underlying atherogenic dyslipidemia, the question of the causes of fatty liver naturally must be addressed. Undoubtedly, fatty liver can arise in several ways. For example, defects in fatty acid oxidation can lead to an increased triglyceride content of the liver. Some defects of fatty acid oxidation are genetic[52,53,54] and others are acquired.[55,56] The form of hepatic lipid overload that is most likely to be accompanied by atherogenic dyslipidemia is one in which input of lipid into the liver is raised. The major source of excess lipid entering the liver is nonesterified fatty acids (NEFA). (See Box, Adipose Tissue, Insulin, NEFA Relationships.)

Adipose tissue is the predominant source of plasma nonesterified fatty acids (NEFA). In the postprandial state, triglyceride-rich lipoproteins undergo lipolysis mainly through the action of lipoprotein lipase (LPL), which is located on capillary endothelial cells in adipose-tissue beds. Most of the fatty acids released through the action of adipose tissue LPL are immediately taken up into adipocytes and are esterified back into triglyceride. Small amounts of newly released fatty acids bind to albumin and enter the systemic circulation. Most of the NEFA entering plasma is derived from the lipolysis of adipose tissue triglyceride through the action of hormone-sensitive lipase. This enzyme is insulin sensitive. In the postprandial state, when a person's insulin levels are elevated, the enzyme is inhibited, and lipolytic rates are low. In the fasting state, when a person's insulin levels are low, lipolytic rates are high and large amounts of NEFA are released into the circulation.

Although NEFA can be used by a variety of tissues, they have two major fates. The primary site of removal of NEFA is skeletal muscle. NEFA are the predominant energy source for skeletal muscle in the fasting state. The other removal site for NEFA is the liver. Fatty acids derived from NEFA undergo oxidation in the liver and are a major energy source for this organ as well. Any fatty acids not used for energy by the liver are reesterified into triglyceride, which is secreted back into the circulation in the form of very low-density lipoprotein (VLDL)-triglyceride. Triglyceride circulating with VLDL undergoes hydrolysis in adipose tissue by LPL to complete the fatty acid cycle.

Amounts of NEFA released by adipose tissue are highly regulated by insulin levels. However, the quantitative effect of insulin on adipose tissue lipolysis is variable from person to person. Some persons are highly sensitive to insulin, and NEFA release is readily suppressed by only moderate increases in circulating insulin levels. Others are more resistant to the actions of insulin; these persons tend to have high NEFA levels and are said to have insulin resistance of adipose tissue. High levels of plasma NEFA can lead to lipid overload in both skeletal muscle and liver. Lipid overload in skeletal muscle impairs uptake of glucose, a condition called insulin resistance of skeletal muscle. Lipid overload in liver induces atherogenic dyslipidemia and other metabolic risk factors of the metabolic syndrome. Thus, the action of insulin to regulate NEFA by adipose tissue is a key factor in the control of lipid metabolism in both skeletal muscle and liver.


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