Are plant sterols and plant stanols a viable future treatment for dyslipidemia?

KEYWORDS:

• Coronary artery disease
• diet
• HDL cholesterol
• LDL cholesterol
• phytosterolemia
• plant stanols
• plant sterols
• triglycerides

Introduction: what are plant sterols and plant stanols?

Plant sterols and plant stanols are normal components of plants present in all vegetable foods, especially in vegetable oils (corn oil, rapeseed oil, soybean oil, and sunflower oil), seeds, nuts, and cereals. They have similar functions in plants as cholesterol has in human beings. Plant sterols differ from cholesterol in the structure of their side chain, while plant stanols are 5α-saturated derivatives of plant sterols. These structural differences between cholesterol, plant sterols, and plant stanols, even though small, have profound effects on their biological functions, so that they are metabolically different molecules.

Plant sterols/stanols are not synthesized in the human body. The most common plant sterols/stanols are campesterol, sitosterol, sitostanol, and campestanol.

Plant sterols/stanols are taken up from the intestinal lumen into the enterocyte in the same way as cholesterol by a sterol transporter Niemann-Pick C1-Like 1 (NPC1L1). From the enterocyte, however, most of the plant sterols/stanols are pumped back to the intestinal lumen and out of the body by the ATP-binding cassette transporters ABCG5 and ABCG8. Thus, the intestinal absorption efficiency of plant sterols/stanols is very low compared to that of cholesterol, which is about 50%. The absorption efficiency of plant sterols is less than 2% and that of plant stanols less than 0.2% [1]. Consequently, the circulating serum levels of plant sterols and stanols are very low compared to serum cholesterol concentration, so that serum total plant sterol concentrations are <24 µmol/l (1.0 mg/dl), and serum total plant stanol concentrations are even lower, <0.7 µmol/l (0.028 mg/dl) [2].

Plant sterols/stanols in food

The mechanism of action

It is well-known from the 1950s that increasing the dietary intake of plant sterols/stanols lowers serum total and low-density lipoprotein cholesterol (LDL-C) concentrations. The only well-documented hypocholesterolemic mechanism of action of plant sterols/stanols is that when present in large enough quantities in the upper small intestine, they displace cholesterol from the mixed micelles so that cholesterol absorption is partially inhibited [3,4]. But how much dietary plant sterols/stanols are needed?

Naturally occurring plant sterols/stanols in food

A recent European dietary survey reveals that the energy-adjusted mean intake of naturally occurring plant sterols is 296 ± 29 (SD) mg/day (range: 83–966 mg/d) in a large population cohort [5]. The average intake of naturally occurring plant stanols is much lower, <30 mg/day [6]. The natural intake of plant sterols/stanols has no or at most a modest effect on LDL-C concentration. However, their natural intake may not be without clinical impact, since cholesterol metabolism was significantly altered in subjects who consumed 449 mg of plant sterols/2000 kcal daily compared to those who consumed 126 mg of plant sterols/2000 kcal daily [7]. The new finding was that during the larger plant sterol intake, intestinal cholesterol absorption efficiency was lower and cholesterol (neutral sterol) excretion into feces was higher compared with those subjects with low plant sterol intake. The altered metabolic profile may have cardioprotective properties, since high cholesterol absorption efficiency has been demonstrated to associate with increased risk of coronary artery disease (CAD) [8]. The intake of natural phytosterols, however, did not turn out to be cardioprotective nor increase the risk of cardiovascular disease (CVD); in two recent large prospective population-based cohort studies, the energy-adjusted natural phytosterol intake had no effect on the risk of CVD [5,9].

Plant sterols/stanols added in food products and supplements

Dietary modification is an essential and generally recommended means to control elevated LDL-C concentration alone or together with medication. To optimize the hypolipidemic effect of plant sterols/stanols as part of a healthy diet, larger amounts of plant sterols/stanols are needed than occur naturally and they have to be made soluble in food formats, e.g. with esterification. Food products enriched with plant sterols/stanols have been on the market since 1995 pioneered by plant stanol ester margarine. Since then, a large number of different plant sterol/stanol products varying from spreads/margarines to low-fat minidrinks, juice, biscuits, and supplements have been developed. The cholesterol lowering efficacy and safety of these food products has intensely been evaluated. Three large meta-analyses have been published recently including over hundred studies and 7000 subjects [10–12]. Thus, it is well documented that plant sterol/stanol intake of 2 g/day lowers LDL-C concentration by 8–10%. The most recent meta-analysis consisting of 124 randomized controlled clinical studies in adults demonstrated a dose–response effect between the amount of consumed plant sterols/stanols and LDL-C lowering, so that increasing the plant sterol/stanol intake from 0.6 g/day to 3.3 g/day LDL-C was lowered from 6% to 12% [12]. Plant sterols/stanols in general do not affect high-density lipoprotein (HDL) cholesterol or serum triglyceride concentrations, but they decrease serum non-HDL cholesterol concentration, they have no effect on serum inflammation markers [2] or on serum proprotein convertase subtilisin/kexin type 9 concentration [13]. They are well tolerated, and there is a large body of information regarding them safe in long-term use [2].

Novel findings

Plant sterols/stanols and atherosclerosis – lessons from patients with phytosterolemia and inhibition of cholesterol absorption

There is a pending question whether elevated serum plant sterols/stanols are atherogenic. It is frequently considered that phytosterolemia (sitosterolemia), a rare disease with extremely elevated serum and tissue plant sterol/stanol concentrations resulting from mutations in the ABCG5 and ABCG8 transporters, presents a clinical example of the atherogenicity of elevated plant sterols/stanols. Serum total plant sterol/stanol concentrations are about 50–200 fold elevated in phytosterolemia compared with the values in general population, and frequently these patients also have hypercholesterolemia. Because of the rarity of the disease (prevalence approximately 1:10⁶) and the difficulties in diagnosis requiring serum sterol analysis and genetic tests, we lack exact knowledge of the frequency of phytosterolemia, the frequency of atherosclerosis in this disease, and the possible mechanisms of atherosclerosis beyond cholesterol. Thus, it was demonstrated in a recent study including five phytosterolemic subjects [age from 17 to 33 years, plasma sitosterol concentration 0.3–1.1 mmol/l (12–46 mg/dl), and plasma campesterol concentration 0.3 mmol (12 mg/dl)], that in spite of massive hypercholesterolemia and high plant sterol/stanol levels, nobody of the five subjects had clinical symptoms of CVD or positive clinical markers of atherosclerosis [14]. Accordingly, it remains unresolved whether elevated serum and tissue plant sterol levels are atherogenic even in phytosterolemia. It should be mentioned that in normal population, plant sterol consumption does not increase serum plant sterol levels beyond population reference values [15]. Moreover, plant stanol consumption decreases serum plant sterol levels, because plant stanols inhibit not only the absorption of cholesterol but also that of plant sterols.

In animal models, plant sterols/stanols were protective toward atherosclerosis including reduction in arterial lipid accumulation and inhibition of lesion formation and progression [2]. In humans, no hard CAD endpoint studies are available during plant sterol/stanol consumption. The risk of CAD has been evaluated in studies using surrogate markers of atherosclerosis, i.e. endothelial dysfunction and arterial stiffness. In two recent large interventions, the results have varied from no effect to only slight beneficial effects in surrogate markers, but no harmful effects were recorded [16,17]. These results suggest that there is no final answer whether plant sterol/stanol consumption is associated with clinical outcome benefit.

However, high cholesterol absorption is suggested to increase the risk of CAD, and there is recent evidence that by reducing intestinal cholesterol absorption, cardiovascular outcomes are improved [8,18]. Thus, the inactivating mutations in NPC1L1 cholesterol transporter protein results in diminished cholesterol absorption, low LDL-C concentration, and protection from CAD [8]. The lessons from the IMPROVE-IT study demonstrated that reducing cholesterol absorption by approximately 40% with ezetimibe when added to statin treatment diminished LDL-C concentration by 24% (−0.3 mmol/l/−12.8 mg/dl) and decreased the vascular event rate by 6.4% compared to the statin-only group [18]. Phytosterol consumption 2 g/day reduces cholesterol absorption by the same amount as ezetimibe.

New hypothesis – inhibition of cholesterol absorption and nonalcoholic fatty liver disease

An intriguing new hypothesis suggests that reduced intestinal cholesterol absorption can ameliorate fatty liver. In animal studies, loss of NPC1L1 expression leading to markedly reduced cholesterol absorption protected against diet-induced fatty liver, and plant sterols added to high-fat diet reduced hepatic inflammation [19]. The question is whether it is possible to reduce liver fat and inflammation also in human nonalcoholic fatty liver disease (NAFLD), a common liver disease associated with insulin resistance and risk factors of CAD. In preliminary uncontrolled clinical studies, ezetimibe reduced liver fat in NAFLD patients. However, in a recent controlled, randomized intervention, ezetimibe was not better than placebo in reducing liver fat or improving liver histology in NAFLD [20]. Accordingly, the hypothesis that an inflammatory liver disease can be treated by reducing cholesterol absorption needs to be investigated further.

In conclusion, the future seems viable for the plant sterols/stanols as a dietary means to treat hypercholesterolemia. Based on the 20 years of experience and intensive research, it is evident that consumption of plant sterols/stanols 2 g/day is a valuable dietary means to lower LDL-C concentration in subjects with low or intermediate global cardiovascular risk as well as an adjunct to pharmacologic therapy in high- and very high-risk patients in prevention of CVD.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.