Invited critical reviewTriglycerides and gallstone formation
Introduction
Alterations in bile acid (BA) metabolism and gallbladder function are critical factors in the pathogenesis of gallstones. Gallstones, about 80% of which are cholesterol stones, are common with an estimated prevalence of 10–20% in the adult population, affecting more often women than men. Major risk factors for gallstone formation are age, female sex, pregnancy, obesity, diabetes, rapid weight loss, liver cirrhosis, hemolytic anemia, and the use of certain therapeutic agents, such as estrogens and octreotide.
Patients with visceral obesity, dyslipidemia and insulin resistance are at increased risk for gallstone disease and this may particularly develop in patients with a disturbed triglyceride metabolism. Triglyceride and BA metabolism are linked and patients with hypertriglyceridemia (HTG) are often overweight and insulin resistant. The question which arises is whether HTG per se is a risk factor for gallstone formation or whether it is just associated with this disorder? Treatment of HTG includes first dietary intervention followed by treatment with fibrates or fish-oil if diet alone is insufficient in controlling TG levels. Use of fibrates is, however, also associated with an increased incidence of gallstone disease and may therefore further contribute to the risk for gallstones in HTG patients. In this review specifically highlighted are the role of triglycerides in gallstone formation and the effects of fibrates and fish-oil on bile acid metabolism and gallbladder function in hypertriglyceridemia.
Section snippets
Triglyceride metabolism
Triglycerides and cholesterol play an important role in human metabolism. Triglycerides are mainly used as an energy source in muscles or are stored in adipose tissue. Cholesterol is a key regulator of plasma membrane fluidity and is essential for the synthesis of steroid hormones, bile acids and vitamin D. Triglycerides and cholesterol are packed into water-soluble lipoproteins for transport in the blood stream. Lipoproteins are spherical particles containing a non-polar core consisting of
Bile acid metabolism
Bile acids are produced by hepatocytes and secreted with cholesterol, phospholipids and other constituents as bile fluid in the canaliculi of the liver. By means of these canaliculi the bile flows to the gall bladder where it is stored and concentrated before being released into the lumen of the small intestine, where it acts as a detergent for dietary lipids, cholesterol and fat-soluble vitamins in order to assist in their absorption. Bile acids are re-absorbed from the ileum, return via the
Bile acid and triglyceride metabolism
Bile acid metabolism appears to have a reciprocal relationship with triglyceride metabolism. BA absorbing resins (cholestyramine and cholestipol) further increase plasma triglyceride levels in patients with dyslipidemia [26]. Defective ileal absorption of BAs was found to be the cause of monogenic familial hypertriglyceridemia [27], and decreased BA synthesis is linked to hypertriglyceridemia in CYP7A1 deficiency. The use of CDCA in patients with gallstone disease may also reduce plasma
Gallstone formation
Both bile composition (supersaturation with cholesterol) and gallbladder dysmotility are involved In the pathogenesis of cholesterol gallstones [31], [32]. Delayed emptying prolongs the residence time of cholesterol in the gallbladder resulting in more nucleation and crystallization. Inflammation and hypersecretion of mucin gel in the gallbladder [33], slow large intestinal motility [34] and increased intestinal cholesterol absorption may also contribute to gallstone disease [35], [36].
Triglyceride lowering therapy and gallstone formation
In hypertriglyceridemia TG lowering therapy is essential to prevent cardiovascular disease and in the severe form of HTG (TG > 8–10 mmol/L (700–900 mg/dL)) also to prevent pancreatitis [54], [55]. The first step to be taken in the management of HTG is dietary intervention with special attention to limitation of alcohol and carbohydrate intake, and to weight reduction in case of overweight. Therapy with fibrates or fish-oil should be considered when dietary intervention fails in achieving control of
Conclusions
Hypertriglyceridemia is most often a multifactorial disorder of VLDL metabolism. It is, however, occasionally a monogenic disorder as observed in familial hypertriglyceridemia where reduced ileal absorption of bile acids leads to increased VLDL production, which links this special type of hypertriglyceridemia to bile acid metabolism. In most (multifactorial) HTG patients, an association with overweight and insulin resistance is usually observed with supersaturated (cholesterol) bile and
References (73)
Hypertriglyceridemia, atherogenic dyslipidemia, and the metabolic syndrome
Am J Cardiol
(1998)- et al.
Heterozygosity for Asn291–>Ser mutation in the lipoprotein lipase gene in two Finnish pedigrees: effect of hyperinsulinemia on the expression of hypertriglyceridemia
J Lipid Res
(1996) - et al.
Prevalence of alleles encoding defective lipoprotein lipase in hypertriglyceridemic patients of French Canadian descent
J Lipid Res
(1995) - et al.
DNA polymorphisms of apolipoprotein A-I/C-III and insulin genes in familial hypertriglyceridemia and coronary heart disease
Atherosclerosis
(1987) - et al.
Association of the A-204C polymorphism in the cholesterol 7alpha-hydroxylase gene with variations in plasma low density lipoprotein cholesterol levels in the Framingham Offspring Study
J Lipid Res
(1999) - et al.
Liver X receptor modulators: effects on lipid metabolism and potential use in the treatment of atherosclerosis
Biochem Pharmacol
(2009) Fifty years of advances in bile acid synthesis and metabolism
J Lipid Res
(2009)- et al.
Insulin regulation of cholesterol 7alpha-hydrolase expression in human hepatocytes: roles of forkhead box O1 and sterol regulatory element-binding protein 1c
J Biol Chem
(2006) - et al.
Leptin induces the hepatic high density lipoprotein receptor scavenger receptor B type 1 (SR-B1) but not cholesterol 7α-hydrolase (Cyp7a1) in leptin-deficient (ob/ob) mice
J Biol Chem
(2003) Bile acids: regulation of synthesis
J Lipid Res
(2009)