Sleeve gastrectomy improves HDL function examined by Apo-A1 and atherogenic indices in non-diabetic obese patients

Introduction

Obesity has serious comorbidities that impair the quality of life and shorten the life span¹. Today, obesity is accepted as a multifactorial chronic disease characterized by inflammation and dyslipidemia². Obesity, which has become an epidemic today, can actually be positively affected by even small changes in body weight and living habits³. Sleeve gastrectomy (SG) surgery can reduce the incidence of obesity-related cardiovascular events in addition to weight loss in patients^4,5. Some recent studies have demonstrated the effects of SG on atherosclerosis and vascular endothelial functions^5,6. The functionality of high-density lipoprotein cholesterol (HDL-C) rather than its amount that can be measured in blood is very important in understanding the mechanism of recovery of patients with obesity and bariatric surgery. Numerous studies in the literature have shown that HDL-C functions are impaired by obesity^7,8.

HDL-C is a highly heterogeneous particle. Most of the more than 200 proteins in the HDL-C structure can be associated with obesity. HDL-C is a lipoprotein with antiatherogenic properties as well as anti-inflammatory and many other properties. The main function of HDL-C is to remove excess cholesterol from peripheral tissues and transport it to the liver for metabolism and excretion. In fact, HDL-C functions as an anti-infective, athero-protective, anti-apoptotic and anti-thrombotic agent, and reverses cholesterol flow^9,10. Normal functional HDL-C has a high level of antioxidant activity, enzymes, and anti-inflammatory activity. Atherosclerotic lesions begin with the accumulation of oxidized low-density lipoprotein (Ox-LDL) in macrophages in the artery wall. Antioxidant molecules in the HDL-C structure, mainly paraoxonase-1 (PON-1), can prevent Ox-LDL oxidation in the arterial wall. Apolipoprotein A-1 (Apo-A1) is the main structural protein of HDL-C and makes up 70% of its proteins. Numerous studies have also shown that Apo-A1 is a powerful antioxidant and anti-inflammatory molecule^9-11.

Today, predictive index calculations such as the atherogenic index of plasma (AIP), atherogenic index (AI), and lipoprotein combined index (LPCI) have been developed to predict the risk of future cardiovascular disease (CVD). However, studies using the CVD risk predictive index in obese patients undergoing SG are few in the literature. In one study, a significantly higher AIP was reported in subjects with abdominal obesity than in subjects without abdominal obesity¹². In another study, a higher AIP level was positively and strongly associated with obesity. In addition, the AIP index can decrease rapidly and significantly with obesity surgery^13,14.

However, there is no study yet showing the effect of SG surgery on functional molecules in the HDL-C structure, such as platelet-activating factor acetylhydrolase (PAF-AH), PON-1, or Apo-A1, which can show antiatherogenic activity. In addition, the possible relationship between the calculated atherogenic risk indices (AIP, AI, and LPCI) and SG surgery is not yet known. This preliminary study may contribute to the improvement of HDL-C functionality and understanding the possible antiatherogenic effects of SG surgery.

Method

Results

The demographic characteristics of the patients are shown in table 1. The mean blood TG levels of the patients were 151 mg/dL pre-operatively (IR: 104.25-199) and 120 mg/dL (IR: 102.25-160.5) post-operatively (3^th month) (p = 0.034). The blood TG values of the patients at the 6^th post-operative month were 99 mg/dL (IR: 84.2-129.75) and were significantly lower than the pre-operative values (p < 0.001). As a result, the blood TG levels of the patients after SG showed a statistically significant decrease from the 3^rd month, as shown in table 2.

Table 1. General characteristics of the patients and comorbidities

Table 2. Pre- and post-operative 3^rd and 6^th months statistical data of TG, TC, HDL-C, and LDL-C

The pre-operative TC levels of the patients were within normal limits (188 mg/dL, IR: 159.5-212.5). Unlike TG values, TC values were 203 mg/dL (IR: 168.25-223.25) and 204 mg/dL (IR: 175.5-241.5) at the 3^rd and 6^th months post-operatively, respectively, yet this slight increase was not statistically significant. The blood HDL-C level of the patients increased from 40 mg/dL pre-operatively (IR: 36.5-47.25) to 44 mg/dL (IR: 39.75-48) at the 3^rd post-operative month (p = 0.091). The increase in HDL-C continued 6 months post-operatively, and HDL-C levels were 48 mg/dL (IR: 45.75-51.5, p < 0.001 and p = 0.004) (Table 2).

Contrary to what was expected in pre-operative patients, the serum LDL-C level increased from 121 mg/dL (IR: 97.56-137) to 133 mg/dL (IR: 118.28-143) at the 3^rd post-operative month. Moreover, this increase in LDL-C was statistically significant at 3 months (p = 0.008). At 6 months post-operatively, LDL-C increased to 134 mg/dL (IR: 118-163.25) and significantly increased compared to pre-operative values (p = 0.02). Although there was no statistically significant difference between the 3^rd and 6^th months (p = 0.1) (Table 2), the slight increase continued. Apo-A1 blood values, which are abundant in the HDL-C structure in pre-operative patients, averaged 2.28 mg/mL (IR: 1.97-3.47). This increase in Apo-A1 level was not statistically significant at 2.59 mg/mL (IR: 2.08-3.07) at the 3^rd post-operative month (p = 0.47). However, the mean blood Apo-A1 level was found to be 2.61 mg/mL at 6 months after SG (IR: 2.31-3.04). As a result, Apo-A1 levels increased at 6 months post-operatively compared to pre- and post-operative levels at 3 months (p = 0.028 and p = 0.05).

Apo-A1, Ox-LDL, PON-1, and PAF-AH values are shown in table 3. However, as shown in figure. 1, the Ox-LDL levels that we used as an oxidative stress (OS) marker in the blood at the 3^rd post-operative month were 440.48 ng/L (IR: 400-659) in pre-operative patients, while the Ox-LDL level was 432.77 ng/L at the 3^rd month. (IR: 382-517). This minimal decrease was not statistically significant (p = 0.46). However, the mean Ox-LDL level decreased to 426.98 ng/L (IR: 377-618) at 6 months post-operatively, but this decrease in Ox-LDL was not statistically significant compared to pre- and post-operative 3 months (Table 3 and Fig. 2).

Table 3. Changes in Apo-A1, Ox-LDL, PON-1, and PAF-AH pre-operative and 3^rd and 6^th months post-operative

Figure 1. Apolipoprotein A-1 distribution by pre- and post-operative 3^rd and 6^th months. In the box-and-whisker plot, the central box represents the values from the lower to upper quartile (25-75 percentile). The middle line represents the median. The horizontal line extends from the minimum to the maximum value, excluding outside and far-out values, which are displayed as separate points.

Figure 2. Oxidized low-density lipoprotein distribution by pre- and post-operative 3^rd and 6^th month. In the box and whisker plot, the central box represents the values from the lower to upper quartile (25-75 percentile). The middle line represents the median. The horizontal line extends from the minimum to the maximum value, excluding outside and far-out values, which are displayed as separate points.

The PON-1 enzyme level in the HDL-C structure showed a significant decrease compared to pre-operative levels at the 3^rd and 6^th months. For example, at the 3^rd post-operative month, its level was 23.64 ng/mL (IR: 17.98-35.38) (p = 0.038). The decrease continued, and the mean PON-1 values decreased to 20.88 ng/mL (IR: 17.33-27.17) in the 6^th post-operative month, and a significant decrease was found according to the pre-operative values (p = 0.05). According to the results, the blood PON-1 enzyme level decreased in pre-operative patients in the 3^rd month, and the decrease slowed down in the 6^th month and maintained the same level. Statistically, the amount of PON-1 did not show a significant change between the 3^rd and 6^th months post-operatively (p = 0.85). There was a strong statistically significant correlation between PON1, Ox-LDL, and Apo-A1. The amount of Ox-LDL and PON-1 enzyme in the correlation calculations is shown in table 4. The reduction in PON-1 is compensatory, perhaps due to the reduced need for Ox-LDL. As a result, the distribution of Ox-LDL and PON-1 values can be seen in figures 2 and 3. However, there was no statistically significant change in the antioxidant enzyme PAF-AH levels in the blood HDL-C structure after SG in the 6^th month (p = 0.5).

Table 4. Correlation of Ox-LDL and the amount of PON-1 enzyme

Figure 3. Paraoxonase-1 enzyme distribution by pre- and post-operative 3^rd and 6^th months. In the box-and-whisker plot, the central box represents the values from the lower to upper quartile (25-75 percentile). The middle line represents the median. The horizontal line extends from the minimum to the maximum value, excluding outside and far-out values, which are displayed as separate points.

One of the most important findings is the atherogenic risk indices that decreased with SG. As a result, the calculated atherogenic risk index values continued to decrease in pre-operative patients from the 3^rd month and reached their lowest levels at the 6^th month. In particular, AIP dropped from a high-risk level to a low-risk level.

Similarly, AI (p = 0.012) and LPCI (p = 0.042) levels decreased significantly post-operatively (Table 5).

Table 5. Statistical improvement of AIP, AI, and LPCI

Discussion

The main findings of this study were that HDL-C and Apo A1, which are indicators of HDL-C function, increased significantly after SG, and patients had a better lipid profile than pre-operative values. Furthermore, there was a strong correlation between Ox LDL and PON-1 as a result of reduced OS. Furthermore, new atherogenic risk indices AIP, AI, and LPCI, which were not included in the literature for SG and were shown comprehensively for the 1^st time in the current study, decreased after SG surgery. Thus, the significant improvement in atherogenic risk indices after SG surgery may demonstrate the strong corrective effect of SG on lipid metabolism in patients with obesity. In the 6^th month after SG, the AIP value of the patients decreased from the risk level to the lower risk level. The patients in the pre-operative group had a high risk of AIP, such as 0.22. In addition, the AI value and especially the LPCI values decreased significantly at the end of the 6^th month. This decrease in atherogenic risk indices is actually an indication that HDL-C functions have improved significantly.

Today, every patient with morbid obesity should be examined for lipid metabolism. Increased TGs, mixed dyslipidemia associated with LDL-C and Ox-LDL, and increased atherogenic risk should be expected in obesity¹⁵. Increased adipose tissue in obese individuals contributes to low-grade inflammation and OS^3,16. Significantly decreased TG levels and increased HDL-C and Apo-A1 levels after SG surgery determined in this study are perhaps the most important reasons for the decrease in atherogenic risk indices. In this study, the most important contribution to HDL-C functions after SG was the significant increase in the amount of Apo-A1 after 6 months.

Conversely, SG surgery can cause a clear reduction in chronic inflammation and atherogenic risk indices by decreasing plasma oxidative markers, including Ox-LDL and PAF-AH enzyme activity, as shown in this study. Our results show that the proatherogenic lipid profile and increased atherogenic risk indices (AIP, AI, and LCPI) characteristic of morbid obesity patients improve after SG^12-14.

In general, an increase in HDL-C was observed in the 3^rd month after SG. There was also a significant decrease in TG levels, which reduced dyslipidemia. However, there was no statistically significant change in TC and Ox-LDL after SG surgery. Increasing systemic bile acid levels and changing bile acid composition after SG can affect lipid absorption, but the molecular mechanism is not understood. In addition to the surfactant role of bile after SG, bile acids also function as signaling molecules for a number of cellular nuclear receptors and plasma membrane receptors¹⁷. SG is a bariatric surgery technique that preserves the small intestine (especially the jejunum), so it may cause a significant increase in HDL-C^4,18.

In our study, we did not find any statistically significant changes in Ox-LDL and PAH enzyme levels in the blood for up to the 6^th month. However, the Ox-LDL levels in the blood of patients with SG did not change significantly. In fact, this result should be expected, since the enzyme PAF-AH in the blood is mainly contained in LDL-C content of more than 80%, but < 20% is associated with HDL-C. Decreased chronic inflammation and decreased production of OS in the blood after SG can contribute to the stabilization of the levels of Ox-LDL and PAF-AH in the blood¹⁹.

According to the literature, HDL-C levels increase by 47% compared to pre-operative SG values 10 years after SG surgery. In our study, the follow-up period after SG was up to 6 months, but even in this short time, the HDL-C ratio increased by 29% compared to pre-operative values. Therefore, an increase in HDL-C values indicates a statistically significant improvement in patients with obesity^20,21. PON-1, which falls in the blood after SG, is actually a multifunctional enzyme associated with HDL-C, contrary to what we expected. PON-1 exerts antiatherogenic effects by increasing cholesterol influx from macrophages to HDL with ATP binding cassette transporter 1. Studies have shown that increased PON-1 activity is associated with a reduction in the incidence of major cardiovascular events^9,22. HDL-C’s most important antiatherogenic effect is thought to occur through macrophage-cholesterol flow and the reverse cholesterol transport system¹⁰. In addition, HDL-C improves endothelial function by increasing nitric oxide production and acts as a protective agent against oxidation and inflammation with Apo-A1- activity^10,22. The main antiatherogenic property of functional HDL-C is inhibition of LDL-C oxidation⁹. Apo-A1, lecithin-cholesterol acyltransferase,and PON-1 enzymes functionally inhibit LDL oxidation in the HDL-C structure^9,10,22. In this study, the amount of PON-1 enzyme found in the blood of patients after SG decreased after the 3^rd month. This enzyme, which acts as an antioxidant in the structure of HDL-C, can mainly function in preventing the formation of Ox-LDL in patients after SG, and there may be a compensatory decrease in the need for PON-1. In fact, a lower level of chronic inflammation, low atherogenic activity, and much less oxidant molecule production should be expected as a result of the reduction in active adipose tissue in patients after bariatric surgery^23,24. The PON-1 enzyme, which acts as an antioxidant in the structure of HDL-C, mainly prevents the formation of Ox-LDL in patients after SG. Finally, the decrease in PON-1 needs after SG surgery may be due to the decrease in radicals of OS synthesis^25,26.

The response of each bariatric surgical procedure to obesity-related dyslipidemia is different. Previous studies have reported a significant decrease in TG and a significant increase in HDL-C and Apo-A1 in patients undergoing SG^26-29. The improvement in insulin sensitivity and the effect of this improvement on lipoprotein lipase activity may be explained by the meaningful and effective decrease in TG levels after SG^26-29. Another finding in our study is that although TC did not change significantly, LDL-C increased significantly from the early post-operative period to the 3^rd month. Fortunately, SG surgery can balance the increase in LDL-C inflammation and OS by reducing oxidative and microvascular function markers in adipose tissue^30,31. Finally, in this study, Ox-LDL levels did not change significantly immediately after surgery and remained without a significant increase at the 6-month follow-up. In one study, a significant increase in HDL-C and Apo-A1 and a decrease in LDL-C and Ox-LDL were observed after the other SG^30-32.

Conclusion

According to our study results, HDL-C levels were increased in patients who had undergone SG surgery. In addition to this numerical increase, the increase in Apo-A1, which is part of the HDL-C function, may be very significant. In addition, the decrease in atherogenic risk indices due to the decrease in Ox-LDL and adipose tissue and the improvement of HDL-C functions after SG may be significant for the anti-atherosclerotic effect of SG surgery and reduce the risk of stroke and cardiovascular events in patients over time. The insufficient number of studies showing the relationship of atherogenic risk indices with SG makes this study a preliminary study, being the first study to report a decrease in atherogenic risk indices after SG surgery and an increase in HDL-C and Apo-A1 serum levels at 3 and 6 months. It is also a preliminary study showing that patients’ HDL-C function improved after SG and significantly reduced TGs and Ox-LDL in the blood. However, it has some limitations; it has a limited number of subjects and longer patient follow-up is not possible.

Funding

The authors declare that they have not received funding.

Conflicts of interest

The authors declare no conflicts of interest.

Ethical considerations

Protection of human and animal. The authors declare that no experiments involving humans or animals were conducted for this research.

Confidentiality, informed consent, and ethical approval. The authors have obtained approval from the Ethics Committee for the analysis of routinely obtained and anonymized clinical data, so informed consent was not necessary. Relevant guidelines were followed.

Declaration on the use of artificial intelligence. The authors declare that no generative artificial intelligence was used in the writing of this manuscript.

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