High cholesterol is usually due to increased numbers of cholesterol-rich lipoproteins, i.e. HDL and LDL. Because VLDL's do contain some cholesterol (12%), high cholesterol can also be seen with very high VLDL concentrations.

• Inherited disorders of lipid metabolism: Familial hypercholesterolemia has been reported in Briards, Rottweilers and Dobermans. Other inherited lipid disorders, e.g. hyperlipidemia of Miniature Schnauzers, hyperchylomicronemia of cats, usually result in increased triglycerides primarily, but you may also see increased cholesterol.
• Diabetes mellitus: Insulin stimulates lipoprotein lipase, which is responsible for hydrolysis of chylomicrons (CM) and VLDL. Insulin also antagonizes hormone sensitive lipase, the hormone responsible for lipolysis of adipose tissue. Insulin lack results in elevated concentrations of CM and VLDL in the blood, with high triglyceride and cholesterol concentrations (although CM and VLDL consist mostly of triglycerides, they also contain small amounts of cholesterol). Lack of inhibition of hormone sensitive lipase causes increased lipolysis, with increased free fatty acid presentation to the liver and VLDL production. In addition, LDL receptors on hepatocytes are downregulated, resulting in increased LDL levels.
  
• Hypothyroidism: In dogs, hypothyroidism is associated with mild to marked elevations in cholesterol, due to increased LDL and HDLs. A cholesterol concentration > 750 mg/dL is associated with a risk of atherosclerosis. Thyroid hormone (T3) stimulates LDL receptors (and promotes uptake of cholesterol), therefore lack of thyroid hormone results in decreased LDL receptors and decreased LDL (cholesterol) uptake.
• Nephrotic syndrome: This is characterized by edema, hypoalbuminemia, hypercholesterolemia and albuminuria and is caused by glomerular damage, e.g. amyloidosis, immune-complex glomerulonephritis. There is an increase in HDL and LDL in this syndrome, although the exact mechanism is unknown (? decreased albumin stimulates cholesterol-rich lipoprotein production, ? defective VLDL removal from circulation).
• Hyperadrenocorticism: Hypercholesterolemia is due to increased LDL, thought to be due to peripheral insulin resistance and down-regulation of LDL receptors in the liver. Corticosteroids also stimulate hormone-sensitive lipase, resulting in increased lipolysis and VLDL production.
• Cholestasis: In hepatobiliary disorders, especially those causing extrahepatic cholestasis (e.g. bile duct obstruction), increased cholesterol (with a unique lipoprotein class called lipoprotein-X) may be seen.
  
• Pancreatitis: Although hypertriglyceridemias are more common in this disorder, high cholesterol may be seen concurrently due to inhibition of lipoprotein lipase.
• Miscellaneous: Drugs (e.g. corticosteroids, methimazole), post-prandial (mild increases in cholesterol may be seen, although values will usually not be elevated outside reference intervals).
  

Low cholesterol can be due to decreased numbers of cholesterol-containing lipoproteins (LDL, HDL, VLDL) or a decreased cholesterol content of these lipoproteins.

• Decreased absorption: Malabsorption and maldigestion problems, e.g. protein losing enteropathies, exocrine pancreatic insufficiency.
• Decreased production: Since the liver is the main site of cholesterol production, low cholesterol values can be seen in chronic liver diseases (e.g. cirrhosis), synthetic liver failure (acute or chronic), and portosystemic shunts (acquired or congenital). Inflammatory cytokines (e.g. IL-1, IL-6, TNFa) can also decrease hepatic synthesis and secretion of lipoproteins.
• Altered metabolism: Inflammatory cytokines can reduce the cholesterol content of lipoproteins by decreasing lecithin-cholesterol acyltransferase activity (the enzyme responsible for converting free cholesterol to cholesterol ester which is then incorporated into HDL and LDL). Similarly, inflammatory cytokines can reduce lipoprotein lipase activity (the enzyme facilitates the conversion of VLDL to LDL). This would lower cholesterol through decreased lipoprotein number and cholesterol content.
  
• Increased uptake of lipoproteins: Upregulation of LDL-receptors on cells (peripheral tissues and liver) can potentially lower cholesterol values. This occurs in rapidly proliferating tumor cells (e.g. acute myeloid leukemia in human patients) and in response to inflammatory cytokines (some acute phase proteins in human patients, such as serum amyloid A, enhance LDL removal from the circulation in acute phase reactions).

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