Inflammation, not Cholesterol, Is a Cause of Chronic Disease

As a primarily lipophilic molecule, cholesterol is not easily transported in blood due to its poor solubility and thus is packaged into lipoproteins which are composed of a lipid core, containing cholesterol esters and a hydrophilic outer phospholipid membrane, allowing for the transport of non-polar lipid molecules (such as cholesterol and triglycerides) around the body to cells that require them.  

There are 5 classes of plasma lipoproteins which include: chylomicrons, very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). Two-thirds of circulating cholesterol is found within LDL particles, as it is the main transporter of cholesterol to the peripheral tissues with HDL molecules performing the opposite function by removing cholesterol and transporting it to the liver for excretion.

Currently, the standard “lipid profile” comprising of plasma cholesterol, LDL cholesterol, HDL cholesterol and serum triglycerides are the biomarkers utilised to test for lipid-related abnormalities and cardiovascular risk. However, recently there has been debate around the relative contribution of an abnormal lipid profile to cardiovascular risk. 

The cholesterol/lipid hypothesis

The difficulties involved in elucidating the contribution of underlying cellular and molecular pathways to the development of chronic disease have often misled the scientific and medical communities. Easily observed statistical and epidemiological correlations of traditional risk factors, can be mistakenly attributed as causative agents of the disease.

According to the ‘cholesterol hypothesis’, high blood cholesterol is a major risk factor for cardiovascular disease, whilst lowering cholesterol levels can reduce risk. Indeed, high levels of LDL and non-HDL cholesterol have been associated with cardiovascular risk, while HDL cholesterol has been considered atheroprotective due to its strong inverse correlation with the progression of CVD. Dyslipidaemias (an abnormal level of lipids or fats in the blood) have been characterised by several studies as a “well established and prominent cause” of cardiovascular diseases.

One-sided interpretations of several epidemiological studies, such as the Seven Countries Study, highlighted the link between saturated fat intake, fasting blood cholesterol, and coronary heart disease mortality. Interpretations of these studies led to the development of the ‘lipid hypothesis’ in which atherosclerosis is considered to be the passive accumulation of cholesterol (specifically LDL cholesterol) into the arterial walls leading to the formation of macrophage-derived foam cells and the development of atherosclerotic plaques.

Dietary and medical guidelines have focused on the reduction of cholesterol and lipid levels as the best way to prevent cardiovascular diseases. However, since cholesterol is an essential biomolecule required for the normal functioning of all human cells, questions have been raised around the degree to which cholesterol levels need to be lowered in order to reduce CVD risk without causing other adverse consequences because of aggressive cholesterol lowering, through statin therapy or avoidance of dietary fats.

Considering that cholesterol and dietary lipids have a range of important bio-functionalities, it has been proposed that lowering cholesterol levels does not equate to better health or lowered risk of CVD. Recent systematic reviews and meta-analyses have started to question the validity of the lipid hypothesis, suggesting that the benefits of statin treatment may have been exaggerated, and there may be an urgent need for a re-evaluation of the guidelines for cardiovascular prevention. Targeting a risk factor such as high serum cholesterol may decrease the probabilities for a disease, but usually cannot prevent the causation of chronic diseases.

The Mediterranean diet and inflammation

It has been observed that CVD and cardiovascular mortality occurs at a much lower rate in southern European populations, despite a relatively high dietary intake of saturated fats and cholesterol. The relationship between dietary cholesterol, total fats and antioxidants likely play a more significant role in the onset and prevention of cardiovascular diseases. Such a low prevalence of cardiovascular mortality of the Mediterranean cohorts of the Seven Countries Study, is now attributed to their lifestyle and dietary habits. Recent research has found the Mediterranean diet (Met-diet) to be protective against a host of chronic inflammatory diseases including secondary CVD prevention, and it is the modulation of the inflammatory milieu associated with cardiovascular diseases which is thought to exert the largest protective effect.

The overall beneficial effects of the Met-diet have radically shifted the attention from the lipid-centric model, characterised by the desire to reduce cholesterol levels, to a model that effectively targets the factual causative factors of chronic disease, namely inflammation and its associated manifestations.

Chronic inflammation as a cause of chronic disease

Inflammation is a physiological response of the innate immune system, which attempts to maintain internal homeostasis, to changing environmental pressures. Triggers can originate from mechanical, physical, chemical, infectious, immunological, traumatic injury or metabolic dysfunction. The inflammatory response aims to reduce the agent that causes tissue injury and/or minimise these effects, and facilitate wound healing and tissue repair to restore homeostasis. Provided the immune response succeeds in eliminating the infectious agent, or to repair the initial tissue injury, the inflammatory process will be terminated, and therefore only affects tissue function transiently. In cases where the inflammation fails to resolve due to the persistence of the triggering agent, or due to unsuccessful repair of the initial tissue injury, a sustained inflammatory process develops, leading to further tissue dysfunction and the development of chronic disease. It is now well established that chronic and unresolved inflammatory manifestations appears to be the key causative agent, at the molecular and cellular level, triggering the onset and development of chronic diseases such as atherosclerosis and subsequent CVD, ischemic and renal disorders, cancer, diabetes, infections and a host of other co-morbidities.

In cases of dyslipidaemia, it is not increasingly understood that elevated cholesterol levels are not the causative agent or biochemical mechanism responsible for endothelial dysfunction and atherosclerosis development. Rather, during chronic inflammatory diseases, inflammation and infections can induce a variety of alterations to lipid metabolism, including decreases in serum HDL cholesterol, and increases in triglycerides and LDL levels. In addition to affecting serum lipid levels, inflammation also adversely affects lipoprotein function, and LDL is more easily oxidised, as the ability of HDL to prevent the oxidation of LDL is diminished. In response to increased plasma LDL cholesterol, an inflammatory response at the endothelial cell wall functions to remove excess LDL and oxidised LDL from circulation to the sub-endothelium where they are engulfed by monocytes for final removal. It is observed that the greater the severity of the underlying inflammatory disease, the more consistently these abnormalities in lipids and lipoproteins are observed.

It is also now recognised that multiple cellular immune factors associated with chronic inflammation can promote endothelial dysfunction and atherogenesis, concomitant with dyslipidaemia or independent of dyslipidaemia. Whilst atherosclerosis was previously understood to be a lipid storage disease, it is now recognised that inflammation drives much of the endothelial dysfunction and the resulting clinical complications and comorbidities, independent of traditional risk factors such as serum lipid levels.

In summary, inflammation plays a key role in all stages of the formation of vascular lesions, which is then maintained and exacerbated by triggering or other risk factors such as poor dietary and lifestyle habits, smoking, hyperlipidaemia/hypercholesterolaemia, hypertension, autoimmune diseases, etc. Adoption of dietary patterns such as the Met-diet provides bioactive food constituents with pleiotropic beneficial effects that extend beyond the mere modulation of serum cholesterol and lipoprotein levels, namely anti-inflammatory and anti-oxidative effects. Micronutrients, phytonutrients, vitamins and anti-inflammatory lipids beneficially affect the levels, activities, and metabolism of key inflammatory mediators implicated in numerous chronic diseases including cardiovascular disease. Whilst cholesterol modulation may be a target of treatment, it is done so through a renewed scientific logic, which targets the underlying drivers of disease progression.

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Source: Tsoupras, A., Lordan, R., Zabetakis, I. Inflammation, not Cholesterol, Is a Cause of Chronic Disease, Nutrients 2018, 10, 604;  doi:10.3390/nu10050604