Elsevier

Clinica Chimica Acta

Volume 411, Issues 21–22, 11 November 2010, Pages 1625-1631
Clinica Chimica Acta

Invited critical review
Triglycerides and gallstone formation

https://doi.org/10.1016/j.cca.2010.08.003Get rights and content

Abstract

Changes in bile acid (BA) metabolism and gallbladder function are critical factors in the pathogenesis of gallstones. Patients with hypertriglyceridemia (HTG) – often overweight and insulin resistant – are at risk for gallstone disease. The question arises whether HTG itself contributes to gallstone formation or whether gallstone disease only associates with this disorder.

Triglycerides are formed in response to fluxes of non-esterified fatty acids and glucose. Hypertriglyceridemia results from either overproduction of triglycerides by the liver, impaired lipolysis or a combination of both. Hyperinsulinemia, as observed in the insulin resistant state, stimulates very low-density lipoprotein (VLDL)-triglyceride synthesis. Peroxisome proliferator-activated receptors (PPARs), liver X receptors (LXRs), farnesoid X receptor (FXR) and hepatocyte nuclear factor 4α (HNF4α) are the nuclear receptors involved in the regulation of lipogenesis. Microsomal triglyceride transfer protein (MTP) is involved in the production of VLDL and its activation is also under control of transcription factors as FXR and Forkhead box-O1 (FoxO1).

Triglyceride and BA metabolism are linked. There is an inverse relationship between bile acid fluxes and pool size and VLDL production and SHP (small heterodimer partner) and FXR are the link between BAs and TG metabolism. BAs are also ligands for FXR and G-protein-coupled receptors, such as TGR5. FXR activation by BAs suppresses the expression of MTP, transcription factor sterol regulatory element binding protein (SREBP)-1c and other lipogenic genes. LXRs stimulate lipogenesis whereas FXRs inhibit the metabolic process.

Synthesis of BAs from cholesterol occurs either via the classical pathway (7α-hydroxylation of cholesterol; CYP7A1) or via the alternate pathway (CYP39A1 or CYP7B1). BAs induce FXR, which inhibits CYP7A1 transcription by activation of SHP and inhibition of HNF4α transactivation.

Bile composition (supersaturation with cholesterol), gallbladder dysmotility, inflammation, hypersecretion of mucin gel in the gallbladder and slow large intestinal motility and increased intestinal cholesterol absorption may contribute to the pathogenesis of cholesterol gallstones. In HTG patients supersaturated bile may be related to the presence of obesity rather than to HTG itself.

Contraction and relaxation of the gallbladder are regulated by neuronal, hormonal and paracrine factors. Postprandial gallbladder emptying is regulated by cholecystokinin (CCK). Poor postprandial gallbladder contraction may be due to the magnitude of the CCK response and to the amount of CCK receptors in the gallbladder smooth muscle cells.

In the fasting state gallbladder motility is associated with the intestinal migrating motor complex (MMC) activity and with elevated plasma motilin levels. Fibroblast growth factor (FGF19), produced on arrival of bile acids in the ileum, is also important for gallbladder motility. Gallbladder motility is impaired in HTG patients compared to BMI matched controls. There is evidence that the gallbladder in HTG is less sensitive to CCK and that this sensitivity improves after reversal of high serum TG levels by use of TG lowering agents. In hypertriglyceridemia TG lowering therapy (fibrates or fish-oil) is essential to prevent cardiovascular disease and pancreatitis. Fibrates, however, also increase the risk for cholelithiasis by increasing biliary cholesterol saturation and by reduction of bile acid synthesis. On the other hand fish-oil decreases biliary cholesterol saturation. Fish-oil may increase bile acid synthesis by activation of 7alpha-hydroxylase and may inhibit VLDL production and secretion through activation of nuclear factors and increased apoB degradation. In HTG patients, gallbladder motility improves during bezafibrate as well as during fish-oil therapy. The question remains whether improvement of gallbladder motility and increased lithogenicity of bile by bezafibrate therapy counteract each other or still result in gallstone formation in HTG patients.

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

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