Effects of Persistent Hyperlipidemia

5. Effects of Persistent Hyperlipidemia

Long-term effects of hyperlipidemia in cats are unknown. Cats are resistant to the development of atherosclerosis compared to humans, due to differences in lipoprotein metabolism between the species. Experimental atherosclerosis has been induced in cats by feeding a diet containing 30% fat, 3% cholesterol (as fed) for 2 to 8 months (Ginzinger et al, 1997).

Atherosclerosis

Atherosclerosis is a specific type of arteriosclerosis with deposition of lipid and cholesterol in the arterial tunica intima and tunica media (Liu et al, 1986). It is unclear however, whether cats with inherited hyperchylomicronemia are at increased risk for the development of atherosclerosis. Studies of lipoprotein interactions with arterial walls have shown that large lipoprotein molecules such as chylomicrons and VLDL have a low influx into the intima (Nordestgaard et al, 1992). Thus inherited hyperchylomicronemia may not be associated with premature atherosclerosis (Ebara et al, 2001).

An increased incidence of atherosclerosis has been noted in association with causes of secondary hyperlipidemia in dogs and humans, but has not been reported in cats. This may be due to the low incidence of some causes of secondary hyperlipidemia in the cat, such as hypothyroidism where there has been evidence for associated atherosclerosis in the dog.

Pancreatitis

There is evidence that persistent hyperlipidemia may lead to pancreatitis (Dominguez-Munoz et al, 1991), and pancreatitis often occurs in humans with inherited hyperchylomicronemia and LPL deficiency. A burst of free radical activity in pancreatic acinar cells disrupts glutathione homeostasis and may be the initiating event in pancreatitis (Guyan et al, 1990). Increased free radical activity may relate to pancreatic ischemia resulting from sluggish pancreatic microcirculation due to high concentrations of chylomicrons (Sanfey et al, 1984). Free radical damage causes leakage of lipase into pancreatic microcirculation. Lipase causes hydrolysis of triglyceride present in excess chylomicrons or VLDL resulting in release of free fatty acids which are intensely inflammatory. Free fatty acids can also cause activation of Hageman factor, or may bind calcium leading to microthrombi and capillary damage. Phospholipid present in chylomicrons and VLDL are also susceptible to free radical attack leading to lipid peroxidation, intensifying inflammation. This results in an increase in release of pancreatic lipase and further lipolysis, leading to pancreatitis (Havel, 1969).

Diabetes Mellitus

Persistent hyperlipidemia may also cause diabetes mellitus (Sane & Taskinen, 1993), and diabetes mellitus has been noted as a sequel to inherited hyperchylomicronemia in humans. Increased triglyceride and free fatty acids may lead to insulin resistance due to inhibition of glucose oxidation and glycogen synthesis (Boden, 1997). Free fatty acids may stimulate glyconeogenesis which contributes to inappropriate glucose production (Rebrin et al, 1995). Increased free fatty acids early on act to stimulate insulin production even with low glucose concentrations. In the long term, increased free fatty acids modulate‚ β-cell gene expression and inhibit insulin secretion (Prentki & Corkey, 1996). By multiple mechanisms, increased serum triglyceride and free fatty acids can lead to hyperglycemia and diabetes mellitus. If hyperlipidemia is corrected, diabetes mellitus caused by hyperlipidemia can be reversed (Mingrone et al, 1999).