Abstract
New drugs targeting bile acid metabolism are currently being evaluated in clinical studies for their potential to treat cholestatic liver diseases, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Changes in bile acid metabolism, however, translate into an alteration of plasma cholesterol and triglyceride concentrations, which may also affect cardiovascular outcomes in such patients. This review attempts to gain insight into this matter and improve our understanding of the interactions between bile acid and lipid metabolism. Bile acid sequestrants (BAS), which bind bile acids in the intestine and promote their faecal excretion, have long been used in the clinic to reduce LDL cholesterol and, thereby, atherosclerotic cardiovascular disease (ASCVD) risk. However, BAS modestly but consistently increase plasma triglycerides, which is considered a causal risk factor for ASCVD. Like BAS, inhibitors of the apical sodium-dependent bile acid transporter (ASBTi’s) reduce intestinal bile acid absorption. ASBTi’s show effects that are quite similar to those obtained with BAS, which is anticipated when considering that accelerated faecal loss of bile acids is compensated by an increased hepatic synthesis of bile acids from cholesterol. Oppositely, treatment with farnesoid X receptor agonists, resulting in inhibition of bile acid synthesis, appears to be associated with increased LDL cholesterol. In conclusion, the increasing efforts to employ drugs that intervene in bile acid metabolism and signalling pathways for the treatment of metabolic diseases such as NAFLD warrants reinforcing interactions between the bile acid and lipid and lipoprotein research fields. This review may be considered as the first step in this process.
Highlights
There are numerous lines of evidence showing that changes in bile acid metabolism can affect atherosclerosis
Data from available literature uniformly indicate that increasing bile acid synthesis with Bile acid sequestrants (BAS) reduces plasma total cholesterol and LDL-C levels, with variable effects on high-density lipoproteins (HDL)-C
The effects of apical sodium-dependent bile salt transporter (ASBT) inhibitors are quite similar to those obtained with BAS, which could be expected because both drug classes increase faecal bile acid loss
Summary
There are numerous lines of evidence showing that changes in bile acid metabolism can affect atherosclerosis. Bile acid sequestrants, which increase faecal bile acid loss by inhibiting their intestinal reabsorption, leading to an increase of bile acid synthesis, were the first class of drugs approved to lower plasma cholesterol to reduce the risk of ASCVD [4,5]. It has become clear that bile acids modulate cholesterol and lipid metabolism as ‘catabolic products’ of cholesterol and facilitators of intestinal lipid absorption and as signalling molecules [7]. We have aimed to gain insight into the effects of these (novel) drugs on plasma lipid metabolism To introduce this topic, we first provide key information on the synthesis of bile acids and their enterohepatic circulation, their role in intestinal lipid absorption, their role as signalling molecules and their role in cholesterol catabolism, while providing a brief description of plasma lipid and lipoprotein metabolism
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