Research Advances With Regards to Clinical Outcome and Potential Mechanisms of the Cholesterol-Lowering Effects of Probiotics

Guo Zhuang; Xiao-Ming Liu; Qiu-Xiang Zhang; Feng-Wei Tian; Hao Zhang; He-Ping Zhang; Wei Chen


Clin Lipidology. 2012;7(5):501-507. 

In This Article

Recent Developments in Mechanism Research

Biosynthesis by the liver and absorption by the intestines are the two major sources of cholesterol in the human body and both of them play an important role in the overall balance of cholesterol. Recent research has found that several pathways may be involved in the mechanisms that govern the cholesterol-lowering effects of probiotics both in vitro and in vivo, but these mechanisms are still not clearly understood.

The Relationship Between Oral Probiotics & the NPC1L1 Protein

Absorption of dietary cholesterol from the intestine is an important part of cholesterol homeostasis. Cholesterol is primarily absorbed in the duodenum and proximal jejunum, while little absorption takes place in the ileal segment of the intestine.[33] The NPC1L1 protein, which is expressed in the brush border membrane of enterocytes in the small intestine, plays a critical role in the absorption of intestinal cholesterol.[34] A substantial reduction in cholesterol absorption was found in NPC1L1-knockout mice, and these mice are completely resistant to diet-induced hypercholesterolemia with plasma lipoprotein and hepatic cholesterol profiles similar to those of wild-type mice treated with the cholesterol absorption inhibitor ezetimibe.[35] Huang et al. administered L. acidophilus ATCC 4356 (109 colony-forming units per day) to 20 male hypercholesterolemic rats for 4 weeks.[36] The authors found a significant (p < 0.05) reduction of expression of NPC1L1 in the duodenum and jejunum. Furthermore, the total and LDL cholesterol concentrations observed in the plasma of the intervention group were significantly decreased compared with the control group (p < 0.05). Duval et al. indicated that NPC1L1 gene expression is downregulated by liver X receptor (LXR) activators in the intestine.[37] LXRs are recognized to be central regulators of cholesterol metabolism in mammals. The two LXRs so far identified, LXRα and LXRβ, are ligand-activated transcription factors belonging to the nuclear receptor superfamily.[37] Huang amd Zheng indicated that the L. acidophilus strain ATCC 4356 could upregulate the expression of LXRα and LXRβ or downregulate the expression of NPC1L1 in a dose- and time-dependent manner in Caco2 cells. NPC1L1 expression did not decrease when LXRs were inhibited by siRNA.[38]

The Relationship Between Oral Probiotics & 3-hydroxy-3-methylglutaryl-CoA Reductase

Inhibition of cholesterol synthesis is the most efficient way to reduce serum cholesterol levels. Cholesterol is synthesized from acetyl-CoA and the biosynthetic pathway is a complex pathway of over 40 cytosolic and membrane-bound enzymes in mammalian cells. The enzyme HMG-CoA reductase, which catalyzes the reduction of HMG-CoA to mevalonate, is the rate-determining enzyme of the cholesterol biosynthetic pathway and has received intense scrutiny as a therapeutic target for the treatment of hypercholesterolemia.[39]

The measurement of HMG-CoA reductase can provide information about the effect of probiotics on hepatic cholesterol synthesis rate. Some studies have demonstrated that supplementation of normal diets with cholesterol or oral statins inhibited HMG-CoA reductase expression.[40] In one study, the authors fed 6-week old C57BL/6 male mice with live or dead L. plantarum strain KCTC3928 daily for 35 days.[41] The results suggested that the LDL cholesterol level was significantly lower, by 42% (p < 0.05), in the group fed live bacteria and that dead L. plantarum KCTC3928 failed to improve plasma lipid profiles (p > 0.05). Therefore, the expression of HMG-CoA reductase was not altered after feeding with probiotics (p > 0.05). Park et al. examined the effects of Lactobacillus acidophilus ATCC 43121 on cholesterol metabolism in hypercholesterolemia-induced rats.[42] The results indicated that supplementation with L. acidophilus ATCC 43121 increased hepatic HMGCoA reductase mRNA expression in the normal diet groups (p < 0.05), but there was no significant difference when L. acidophilus ATCC 43121 was supplemented in hypercholesterol diets (p > 0.05). Unfortunately, only these two studies have investigated the effects of probiotics on HMG-CoA reductase expression. Further studies are required to confirm the relationship between oral probiotic strains and expression of HMG-CoA reductase.

The Relationship Between Oral Probiotics & Cholesterol 7α- & 27α-hydroxylase

Cholesterol can degrade to bile acids in the liver through the classical (neutral) or alternative (acidic) pathway. The classical pathway of bile acid biosynthesis is only present in hepatocytes and the alternative pathway is mainly active in peripheral tissues. In the classical pathway, αhydroxylation occurs on carbon 7 of the cholesterol steroid nucleus. This reaction is catalyzed by the cholesterol 7α-hydroxylase (CYP7A1) and is the rate-limiting step of the biosynthesis of bile acids. In the alternative pathway, cholesterol is oxidized by sterol 27-hydroxylase (CYP27A1) to oxysterols; the oxysterols are then converted to 7α-hydroxylated oxysterols by oxysterol 7α-hydroxylase (CYP7B1). Finally, 7α-hydroxylated oxysterols enter the latter steps of the classical pathway.[43] Jeun et al. indicated that groups fed live Lactobacillus plantarum KCTC3928 showed significant increases in fecal bile acids in C57BL/6 mice and that gene expression and protein levels of CYP7A1 were significantly upregulated (+80% for mRNA and +60% for protein expression), but that this regime had no effect on CYP27A1 gene expression and protein levels when compared with the control group.[41] Park et al. reported that supplementation of normal diets with L. acidophilus ATCC 43121 increased hepatic cholesterol CYP7A1 expression; however, decreased CYP7A1 expression was found in the hypercholesterol diet group.[42]