Role of Cytokines in Inducing Hyperlipidemia

Plasma lipid levels are elevated in people with diabetes, and a direct relationship can be demonstrated between indices of diabetic control and plasma lipid levels. Many observations suggest that diabetes may be associated with enhanced cytokine production, raising the possibility that some of the metabolic abnormalities associated with diabetes may be due to or exacerbated by cytokine overproduction. Tumor necrosis factor induces a rapid increase in serum triglyceride levels caused by an increase in VLDL of normal composition. Although in vitro studies showed that TNF decreases adipose tissue lipoprotein lipase activity, recent studies with intact animals demonstrated that TNF increases serum triglyceride levels by stimulating hepatic lipid secretion, not by affecting clearance. The increase in hepatic VLDL triglyceride secretion induced by TNF is due to both the stimulation of hepatic de novo fatty acid synthesis and an increase in lipolysis. Other cytokines including IL-1, IL-6, and α-interferon increase hepatic de novo fatty acid synthesis. Similarly, cytokines such as IL-1 and α-, β-, and γ-interferon also increase lipolysis. Thus, a variety of cytokines acting at different receptors can affect multiple processes that can alter lipid metabolism and increase serum lipid levels. These cytokine-induced increases in serum lipoprotein levels may be a beneficial response for the host. Studies show that lipoproteins, including VLDL, bind endotoxin and can protect against the toxic effects of endotoxin. Moreover, lipoproteins bind a variety of viruses, reducing their infectivity. Lipoproteins also bind urate crystals, which reduces the inflammatory response induced by these crystals. Thus, it can be postulated that lipoproteins are part of a nonspecific immune response stimulated by cytokines, the hormones of the immune systems, that can decrease the toxicity of harmful biological and chemical agents. Although these changes may have benefit under some circumstances, the overproduction of cytokines in people with diabetes could lead to inappropriate metabolic effects, including hyperlipidemia, that in the long run could have adverse consequences, such as accelerated atherosclerosis.