Updating the lipids hypothesis of inflammation and vascular disease in patients with chronic kidney disease: a stearoyl-CoA desaturase affair?


  • C. Zoccali,

    Corresponding author
    1. Clinical Epidemiology and Pathophysiology of Renal Diseases and Hypertension CNR National Research Council and Renal and Transplantation Unit, Ospedali Riuniti, Italy
    • Correspondence: Carmine Zoccali, FASN, FERA, FAKF, Nefrologia e CNR, Ospedali Riuniti, Reggio Calabria 89124, Italy.

      (fax: +39-096526879; e-mail: carmine.zoccali@tin.it).

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  • F. Mallamaci

    1. Clinical Epidemiology and Pathophysiology of Renal Diseases and Hypertension CNR National Research Council and Renal and Transplantation Unit, Ospedali Riuniti, Italy
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Fatty acids (FAs) are long-chain hydrocarbons of various length. Over 20 types of FAs exist in the most commonly consumed foods. Some FAs fundamental for cell biology are not endogenously synthesized by the human body [such as the ω-3 polyunsaturated FAs (PUFAs)], and therefore represent essential nutrients (essential FAs) that should be consumed in the diet. From a biochemical point of view, FAs are classified into four categories: saturated, monounsaturated, polyunsaturated and trans fats. In saturated FAs (Fig. 1), the hydrogen atoms are fully saturated with the maximum number of carbon (C) bonds available for linking; these FAs are, therefore, maximally hydrogenated. In monounsaturated FAs, all but one C atoms are hydrogenated; the nonhydrogenated C is linked to the contiguous C by a double (unsaturated) bond (Fig. 1). In PUFAs, two or more C atoms (Fig. 1) are connected by a double bond which can exist in the cis (both hydrogen atoms are on the same side of the double bond) or trans configuration (the hydrogen atoms are on opposite sides of the double bond). Spatial orientation with respect to double bonds is biologically important because trans fats – a class of FAs used to increase the shelf life of various types of food – have detrimental effects on human health [1].

Figure 1.

Saturated, monounsaturated and polyunsaturated fatty acids and stearoyl-coA desaturase activity. The activity of this enzyme is modulated by insulin and also by carbohydrates, cholesterol and saturated and polyunsaturated FAs.

Saturated fats and human health

The main sources of dietary saturated FAs are dairy products, fatty meats, palm oil and most processed foods, including meat and cream sauces, pies, soups, stews and bakery products made with lard, butter or whole milk. Replacing saturated FAs in the diet with PUFAs but not with carbohydrates [2] leads to favourable effects with regard to coronary heart disease prevention.

The proinflammatory potential of saturated FAs is well established in experimental models [3] as well in human studies [4]. High saturated fat intake causes expansion of the white adipose tissue by inducing adipocyte hypertrophy and hyperplasia and alters insulin signalling [5]. Adipocytes with a high saturated FA content recruit macrophages and interact with these cells to mount a proinflammatory response. Furthermore, once released into the circulation, proinflammatory cytokines from the adipose tissue and saturated FAs further impair insulin signalling in other nonfat tissues, thus contributing to whole-body insulin resistance of obesity and type 2 diabetes. Hence, local (adipose tissue) and systemic effects of excessive saturated FAs together lead to insulin resistance, a major factor leading to adverse clinical outcome in obese people [5]. These considerations are of relevance for patients with chronic kidney disease (CKD) on dialysis (CKD-stage 5D) as recent surveys have shown that saturated FA intake is excessive in these patients [6, 7], most of whom are obese [8]. Further studies have shown that low PUFA intake is associated with inflammation as well as with a high risk of adverse clinical outcomes in the same population [9].

High stearoyl-CoA desaturase-1 (SCD-1) activity: protective or harmful?

FA content is tightly controlled at the cellular level. In the liver and in fat depots, the iron-containing microsomal enzyme stearoyl-CoA desaturase-1 (SCD-1) converts saturated FAs into monounsaturated FAs, that is, stearic into oleic acid and palmitic into palmitoleic acid [10] .Monounsaturated FAs are the preferred substrates for esterification to cellular triglycerides and, therefore, SCD-1 is central for dividing dietary and endogenous FAs into metabolically active or quiescent pools. A high level of activity of this enzyme has been associated with hypertriglyceridaemia, fat accumulation and obesity, liver steatosis, insulin resistance and diabetes, inflammation and a high risk of cardiovascular disease [10]. Together, these findings suggest that high SCD-1 activity is a risk factor for metabolic disturbances and cardiovascular disease. On the other hand, high SCD-1 activity may also be seen as a protective mechanism to prevent accumulation of saturated FA and the subsequent inflammation and vascular damage. In line with this, the SCD1-deficient mouse is lean and resistant to diet-induced and genetic obesity, with low triglyceride levels and a lack of insulin resistance; however, this mouse develops severe vascular inflammation and atherosclerosis when exposed to a typical western diet [11]. This effect is attributable to the proinflammatory activity of raised very low-density lipoproteins which, due to low SCD-1 activity, become rich in saturated FAs. Similarly, it has recently been shown that saturated FAs in the obese rat heart cause apoptosis and oxidative stress, which are fully reversible by forced SCD-1 expression [12].

As suggested above, clinically increased SCD-1 activity has been associated with hypertriglyceridaemia, obesity, insulin resistance and other endocrine and metabolic disorders. Inhibition of SCD-1 activity has been proposed as treatment for obesity, diabetes and other metabolic conditions [10]. Yet, given the proatherogenic effects of low SCD-1 activity, it remains unclear whether interfering with SCD-1 has potential to treat human diseases [13].

Inflammation and the high risk of death in dialysis patients: a continuing problem

CKD-5D patients have a decupled risk of all-cause and cardiovascular death compared with the general population [14]. Such a risk excess is mainly attributable to CKD-related nonclassical risk factors, including the inflammation–protein wasting complex, bone mineral disorders, overt or subclinical volume expansion and accumulation of uraemic compounds [15]. Inflammation in this population is considered a largely unresolved, multifactorial phenomenon with complex interactions between classical and emerging risk factors [16]. The lipids hypothesis of increased cardiovascular disease risk in dialysis patients [17] has not been confirmed by recent clinical trials of statin treatment [18]. However, fat metabolism is complex and the lack of effect of statins does not exclude the possibility that lipids other than cholesterol may be involved in the pathogenesis of CKD-5D patients. The issue is of relevance as any substance interfering with biological processes for which clearance from the body is directly or indirectly dependent on renal function may easily accumulate and activate inflammatory and toxic effects in patients with advanced CKD. Furthermore, the activities of several enzyme are altered in uraemia, including those essential for glucose and energy metabolism [19].

What this study adds to current knowledge

These considerations are of relevance for CKD because recent surveys show that saturated FA intake is excessive in CKD-5D patients [6, 7], most of whom are obese [8]. In addition, low PUFA intake – a critical factor in the regulation of SCD-1 activity (Fig. 1) – is associated with inflammation as well as with a high risk of adverse clinical outcomes in dialysis patients [9]. In this issue of the Journal of Internal Medicine, Hung et al. [20] show for the first time that high SCD-1 activity is associated with inflammation and death in patients with CKD-5D. To circumvent inherent difficulties with directly measuring SCD-1 activity in a large sample size as in this study, the authors estimated the activity by the palmitoleic (unsaturated FA)/palmitic acid (saturated FA) ratio in phospholipids, which reflects SCD-1 in the liver, and in free FAs, which, reflects the enzyme activity in adipocytes. This is a reasonable choice because dietary palmitoleic acid is low in most western countries, and hence circulating levels largely reflect conversion from palmitic acid by SCD-1. Yet, this is an indirect approach, and thus it cannot be established whether the associations between SCD-1 and inflammation and death depend on high SCD-1 activity per se or on high intake of saturated FAs. Michaelis–Menten kinetics predicts that this ratio increases progressively at increasing concentrations of palmitic acid. Huang et al. did not provide a direct comparison of palmitoleic and palmitic acid levels in CKD-5D patients and in healthy subjects at identical saturated FA intake, which leaves the issue unresolved. Meat and dairy products are an important source of this saturated FA, and because saturated FA intake is high in dialysis patients, [7] this may be indeed the driver of the apparent link between high SCD-1, inflammation and mortality in CKD-5D patients. Whatever the interpretation of this link, findings in this study are important because they support the view that excessive intake of saturated fatty acids and/or disturbed regulation of SCD-1 in patients with CKD-5D may not only be a relevant player in inflammation in this population but also a causative risk factor for the astonishingly high death risk of this condition [14].

Because of the disappointing results of intervention trials aimed at curbing the high mortality in CKD-5D patients [18, 21, 22], renal physicians should increase efforts to test biologically sound interventions that may attenuate the enormous cardiovascular and noncardiovascular risk differential between patients with kidney failure and the general population. In this respect, the hypothesis proposed by Huang et al. [20] would certainly be worth testing. Along with adequate dialysis, appropriate nutrition is an essential part of the treatment of these patients. A randomized clinical trial replacing high saturated FAs with PUFAs while maintaining adequate protein and energy intake in CKD-5D patients is a feasible, worthwhile scientific means for testing the intriguing hypothesis presented by Huang and colleagues.

Conflict of interest

No conflicts of interest to declare.