Effects of adiposity on plasma lipid response to reductions in dietary saturated fatty acids and cholesterol

Abstract

Dietary SFA and cholesterol are major targets for reducing plasma total and LDL cholesterol as a strategy to decrease cardiovascular disease risk. However, many studies show that excess adiposity attenuates the expected lipid and lipoprotein response to a plasma cholesterol-lowering diet. Diets low in SFA and cholesterol are less effective in improving the lipid profile in obese individuals and in patients with metabolic syndrome. In contrast, lean persons are more responsive to reductions in dietary SFA and cholesterol. Multiple mechanisms likely contribute to the altered plasma lipid responses to dietary changes in individuals with excess adiposity. The greater rate of hepatic cholesterol synthesis in obese individuals suppresses the expression of hepatic LDL receptors (LDLR), thereby reducing hepatic LDL uptake. Insulin resistance develops as a result of adipose-tissue induced inflammation, causing significant changes in enzymes necessary for normal lipid metabolism. In addition, the LDLR-mediated uptake in obesity is attenuated by alterations in neuroendocrine regulation of hormonal secretions (e.g. growth hormone, thyroid hormone, and cortisol) as well as the unique gut microbiota, the latter of which appears to affect lipid absorption. Reducing adipose tissue mass, especially from the abdominal region, is an effective strategy to improve the lipid response to dietary interventions by reducing inflammation, enhancing insulin sensitivity, and improving LDLR binding. Thus, normalizing adipose tissue mass is an important goal for maximizing the diet response to a plasma cholesterol-lowering diet.

Figure 1

Excess adipose tissue leads to insulin resistance. Weight gain and excess nutrition increase adipose tissue and adipocyte size. Decreased oxygen delivery and elevated stress occur within the adipocytes, resulting in cell death, initiation of the inflammatory response, and recruitment of macrophages to the site of injury. Exposure to fatty acids can initiate the inflammatory process as well via TLR4 on adipocytes and macrophages. Release of proinflammatory cytokines further activates the inflammatory process in nearby adipocytes, resulting in localized insulin resistance. Proinflammatory cytokines, adipokines, and fatty acids also enter systemic circulation, causing insulin resistance in both liver and muscle.

Figure 2

Lipid metabolism and transport. Dietary fat and cholesterol are transported as chylomicrons through the lymphatic system. LPL hydrolyze TG in chylomicrons, releasing glycerol and FFA. Cholesterol and TG in the liver get packaged and transported as VLDL. Lecithin-cholesterol acyltransferase (LCAT) esterifies free cholesterol (C), forming the core of newly synthesized HDL molecules. CETP transfers TG to HDL in exchange for cholesterol ester (CE), whereas LPL hydrolyzes TG in VLDL, resulting in dense LDL molecules taken up by extrahepatic tissues and/or liver. Lipid-rich HDL gets taken back up by the liver in a process known as RCT. Cholesterol can also be used to synthesize bile acids and/or get excreted. ACAT, acyl-CoA:cholesterol acyltransferase; HL, hepatic lipase.