The Pathophysiological Associations Between Obesity, NAFLD, and Atherosclerotic Cardiovascular Diseases

Abstract

Obesity, non-alcoholic fatty liver disease (NAFLD), and atherosclerotic cardiovascular diseases are common and growing public health concerns. Previous epidemiological studies unfolded the robust correlation between obesity, NAFLD, and atherosclerotic cardiovascular diseases. Obesity is a well-known risk factor for NAFLD, and both of them can markedly increase the odds of atherosclerotic cardiovascular diseases. On the other hand, significant weight loss achieved by lifestyle modification, bariatric surgery, or medications, such as semaglutide, can concomitantly improve NAFLD and atherosclerotic cardiovascular diseases. Therefore, certain pathophysiological links are involved in the development of NAFLD in obesity, and atherosclerotic cardiovascular diseases in obesity and NAFLD. Moreover, recent studies indicated that simultaneously targeting several mechanisms by tirzepatide and retatrutide leads to greater weight loss and markedly improves the complications of metabolic syndrome. These findings remind the importance of a mechanistic viewpoint for breaking the association between obesity, NAFLD, and atherosclerotic cardiovascular diseases. In this review article, we mainly focus on shared pathophysiological mechanisms, including insulin resistance, dyslipidemia, GLP1 signaling, inflammation, oxidative stress, mitochondrial dysfunction, gut dysbiosis, renin-angiotensin-aldosterone system (RAAS) overactivity, and endothelial dysfunction. Most of these pathophysiological alterations are primarily initiated by obesity. The development of NAFLD further exacerbates these molecular and cellular alterations, leading to atherosclerotic cardiovascular disease development or progression as the final manifestation of molecular perturbation. A better insight into these mechanisms makes it feasible to develop new multi-target approaches to simultaneously unhinge the deleterious chain of events linking obesity and NAFLD to atherosclerotic cardiovascular diseases.

Keywords

obesity  - cardiovascular diseases - insulin resistance - endothelial dysfunction - GLP1 signaling

Introduction

Obesity is a growing health concern and a major driver of several metabolic diseases [1]. Previous epidemiological analyses have shown the association of obesity with NAFLD and atherosclerotic cardiovascular diseases [2] [3]. With the spread of Western lifestyle and obesity, NAFLD has become the most common chronic liver disease in recent decades [4] [5]. The number of patients suffering from NAFLD has increased from 391.2 million in 1990 to 882.1 million in 2017 [6]. Atherosclerotic cardiovascular diseases are a major cause of mortality in patients with high body mass index (BMI) [7]. Furthermore, it has been found that NAFLD markedly increases the risk of atherosclerotic cardiovascular accidents, and atherosclerotic cardiovascular diseases are a leading cause of mortality among patients with NAFLD [8]. Even NAFLD in those without obesity and overweight, known as lean NAFLD, is associated with a higher risk of atherosclerotic cardiovascular diseases; however, the association is more robust in the presence of obesity [9] [10].

Consistently, a significant weight loss achieved either by lifestyle modification, medication, or surgery can vigorously lower the risk of NAFLD and atherosclerotic cardiovascular diseases or alleviate the pre-existing disease [11] [12] [13]. Interestingly, a minimum weight loss can also remarkably improve NAFLD in lean patients [14] [15]. Bariatric surgeries, particularly sleeve gastrectomy and Roux en-Y gastric bypass, have been breakthroughs in the management of morbid obesity with tremendous benefits in the resolution of NAFLD, non-alcoholic steatohepatitis (NASH), and liver fibrosis [16]. Besides, bariatric surgeries significantly reduced cardiovascular events and prolonged the overall survival of patients [11]. Newly, the development of semaglutide, a glucagon-like peptide-1 (GLP1) agonist, and tirzepatide, a dual agonist of GLP1 and glucose-dependent insulinotropic polypeptide, also known as gastric inhibitory polypeptide (GIP), revolutionized the treatment of obesity, with simultaneous protective effects on atherosclerotic cardiovascular disease and NAFLD [12] [13] [17] [18] [19]. Interestingly, the newly published study by Jastreboff et al. indicated that retatrutide, a triple agonist of GIP, GLP1, and glucagon receptor, led to greater achievement in the management of obesity with up to –24.2% percentage change in body weight after 48 weeks of treatment [20]. These findings indicate certain pathophysiological links between obesity, NAFLD, and atherosclerotic cardiovascular diseases. A deeper insight into these mechanisms may help develop novel therapeutic strategies. In addition, the promising results of these clinical trials imply that it is not always necessary to identify new therapeutic targets to achieve satisfactory clinical outcomes, and simultaneous targeting of a combination of already-known mechanisms can provide a greater benefit in most cases [12] [13] [17] [18] [19] [20]. Therefore, this review article attempts to dissect the main underlying mechanisms implicated in the association between obesity, NAFLD, and atherosclerotic cardiovascular diseases. We searched PubMed and Google Scholar to identify articles reporting the mechanisms involved in the mutual interaction of obesity, NAFLD, and atherosclerotic cardiovascular diseases. Herein, we used a combination of many keywords for the search. For instance, we used obesity, non-alcoholic fatty liver disease, or cardiovascular disease in combination with major mechanisms, such as insulin resistance, dyslipidemia, inflammation, oxidative stress, mitochondrial dysfunction, gut dysbiosis, renin-angiotensin-aldosterone system (RAAS) overactivity, endothelial dysfunction, or GLP1, as the search terms. We particularly focused on studies published within the last 5 years; however, all studies could be potentially used for writing this narrative review.

Shared mechanisms in the pathogenesis of obesity, NAFLD, and atherosclerotic cardiovascular diseases

Insulin resistance

Obese individuals experience some degrees of insulin resistance [21]. Particularly, visceral fat mass and waist circumference are strongly correlated with insulin resistance [22]. Indeed, insulin resistance is the main link between obesity and its metabolic complications [21]. Furthermore, weight loss was shown to improve insulin sensitivity in obesity [23] [24]. Various mechanisms, such as increased levels of leptin, decreased levels of adiponectin, inflammation, mitochondrial dysfunction, lipotoxicity, and gut dysbiosis, have been implicated in the pathophysiology of insulin resistance in obesity [23] [25] [26].

Insulin resistance is pivotal for developing NAFLD. Also, the presence of NAFLD or its progression predicts more severe insulin resistance [27] [28]. Unstoppable lipolysis in the adipose tissue due to insulin resistance leads to the accumulation of circulating free fatty acids in the liver [29] [30]. NAFLD is associated with increased uptake and synthesis of fatty acids [31]. Ineffective mitochondrial function and fatty acid oxidation can double the problem in NAFLD [31]. Consistently, augmentation of hepatic β-oxidation improves liver steatosis [32]. Hyperinsulinemia and dyslipidemia are more severe in patients with obesity and NAFLD compared to patients with obesity but without NAFLD [28]. Interestingly, Smith et al. uncovered that hepatic de novo lipogenesis in response to intrahepatic triglyceride was 11%, 19%, and 38% in lean, obese, and obese-NAFLD individuals, respectively [33]. They also showed that hepatic de novo lipogenesis was negatively correlated with hepatic and whole-body insulin sensitivity, and positively correlated with insulin level and 24-hour plasma glucose [33]. In addition, a mild improvement of NAFLD was shown to ameliorate insulin resistance of patients [34]. Insulin receptor substrate 2 (IRS-2) is downregulated in the liver of patients with NAFLD/NASH [35]. Furthermore, there is an inverse and robust correlation between the expression of IRS-2 and gluconeogenesis enzymes. However, downregulation of IRS-2 does not decrease fatty acid synthesis in patients with NAFLD [35]. Moreover, it has been shown that plasma membrane sn-1,2-diacylglycerols binds to protein kinase C epsilon type (PKCε) in liver steatosis [36]. PKCε activation eventually results in insulin receptor Thr¹¹⁶⁰ phosphorylation, which impairs insulin sensitivity, decreases glycogen synthesis, and enhances gluconeogenesis [36].

Insulin resistance is the main driver of atherosclerotic cardiovascular diseases. The meta-analysis of eight cohort studies consisting of 5 731 294 individuals unfolded that compared with the lowest triglyceride-glucose index, the highest triglyceride-glucose index was independently associated with a higher risk of atherosclerotic cardiovascular diseases (HR 1.61, 95% CI 1.29–2.01) [37]. Furthermore, an increased risk of atherosclerotic cardiovascular diseases was reported for one unit increment in the triglyceride-glucose index (HR 1.39, 95% CI 1.18–1.64) [37]. Similarly, the meta-analysis of 69 studies comprising 516 325 non-diabetic individuals uncovered that 1 unit increase in glucose and homeostatic model assessment for insulin resistance (HOMA-IR) significantly [relative risk (RR) 1.21, 95% CI 1.13–1.30] and (RR 1.46, 95% CI 1.26–1.69), respectively) increases the risk of coronary heart disease [38]. Insulin resistance impairs endothelial nitric oxide release, overactivates endothelial oxidative stress, deteriorates mitochondrial dysfunction, and augments inflammatory response [39]. The result of these alterations is endothelial dysfunction and vascular remodeling [39] [40]. Moreover, insulin resistance can gradually progress to cardiac hypertrophy, which interferes with normal myocardial function and accelerates myocardial strain and heart failure [40] [41].

Obesity induces insulin resistance, which elevates the risk of NAFLD and atherosclerotic cardiovascular diseases. Furthermore, NAFLD exacerbates the pre-existing insulin resistance, which can accelerate the progression of atherosclerotic cardiovascular diseases.

Dyslipidemia

Previously, it has been shown that obesity is strongly associated with dyslipidemia [42]. Besides, weight loss achieved by lifestyle modification, pharmacotherapy, or bariatric surgery can markedly decrease triglyceride and low-density lipoprotein cholesterol (LDL-C) and increase high-density lipoprotein cholesterol (HDL-C) [43]. Bashar et al. unfolded that 1 kg weight loss with lifestyle modification can lead to –4.0 mg/dl (95% CI, –5.24 to –2.77) change in triglyceride, –1.28 mg/dl (95% CI, –2.19 to –0.37) change in LDL-C and 0.46 mg/dl (95% CI, 0.20 to 0.71) alteration in HDL-C [43].

Dyslipidemia is a major driver of cardiovascular diseases, especially atherosclerotic cardiovascular diseases. Compared with subjects with normal lipid profiles, patients with dyslipidemia are at a higher risk of hypertension (OR 3.05, 95% CI 2.36–3.90) [42]. Fasting hypertriglyceridemia predicts elevated risk of cardiovascular death (OR 1.8, 95% CI 1.31–2.49), cardiovascular events (OR 1.37, 95% CI 1.23–1.53), and myocardial infarction (OR 1.31, 95% CI 1.15–1.49) [44]. Statins, as the most important lipid-lowering drugs, can greatly reduce the risk of cardiovascular events either as a therapeutic or preventive medication [45]. For instance, it was found that the use of a lipid-lowering drug leads to 21% decrease in ischemic stroke [46]. A 50% or more reduction in LDL-C profoundly reduced the risk of ischemic stroke recurrence (OR 0.15, 95% CI 0.11–0.20) in this study [46].

The liver plays a critical role in the metabolism of lipoproteins, and there is a close association between hepatic dysfunction and altered lipoprotein metabolism in patients with NAFLD [47]. NAFLD is associated with increased levels of proatherogenic lipoproteins [48]. Likewise, the fatty liver index (FLI) positively correlates with proatherogenic lipoproteins [48]. Specifically, higher FLI is associated with a greater number and size of very low-density lipoprotein (VLDL) [48]. Furthermore, there is an inverse correlation between FLI and HDL-C [48]. Dowla et al. reported that elevated levels of triglyceride and LDL-C and lower levels of HDL-C are common among children with NAFLD [49]. Interestingly, it was shown that increased risk of dyslipidemia and hyperglycemia are independent of visceral fat mass in NAFLD [50].

De novo lipogenesis plays an important role in the development of NAFLD. Hyperinsulinemia contributes to hepatic de novo lipogenesis [51]. The combination of increased triglyceride synthesis and decreased fatty acid catabolism contributes to liver fat accumulation and dyslipidemia [52].

Obesity and NAFLD are both associated with impaired lipid metabolism. Dyslipidemia gradually presents as atherosclerotic cardiovascular diseases and shortens patients’ survival.

GLP1 signaling

GLP1 is an endogenous incretin produced by the gut in response to food intake [53]. Due to its extensive role in different biological functions and diseases, GLP1 agonists, a class of antidiabetic medications, have received increasing attention [53]. GLP1 suppresses inflammation, promotes insulin secretion and decreases glucagon secretion by the pancreas, mitigates insulin resistance, and enhances thermogenesis [53] [54] [55]. By acting on the central nervous system (CNS), GLP1 induces satiety, suppresses appetite, and decelerates gastric emptying, which led to a pronounced weight-lowering effect in animal studies and clinical trials [56] [57] [58]. For instance, the SELECT trial with 17 604 patients reported that over 104 weeks of randomization, mean body weight decreased by 9.39% with 2.4 mg once-weekly subcutaneous semaglutide, a potent GLP1 agonist, while by 0.88% with placebo [56]. Owing to their vigorous weight-lowering properties and metabolic effects, GLP1 agonists were found to significantly lower blood sugar levels and improve dyslipidemia [56]. In this regard, the SELECT trial indicated that after 104 weeks, semaglutide markedly reduced hemoglobin A1c (HbA1c) (–0.31%), systolic blood pressure (–3.82 mmHg), triglyceride level (–18.34%), LDL-C (–5.25), C-reactive protein (CRP) level (–39.12%), and increased HDL-C (4.86%) in non-diabetic subjects with overweight or obesity [56]. As expected, such extensive metabolic effects were accompanied by a considerable reduction in the risk of non-fatal myocardial infarction [hazard ratio (HR) 0.72, 95% CI (0.61–0.85)], coronary revascularization [HR 0.77, 95% CI (0.68–0.87)], and the composite outcome of death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke [HR 0.80, 95% CI (0.72–0.90)] [56].

Mechanistically, treatment with liraglutide, a GLP1 agonist, improved blood flow to adipose tissue and promoted the expression of insulin receptor in adipocytes, thereby ameliorating insulin resistance [55]. GLP1 receptor stimulation in rats was also shown to activate AMP-activated protein kinase (AMPK), a target of insulin sensitization, in rat liver and promote AMPK-mediated expression of peroxisome proliferator-activated receptor α (PPARα), a nuclear transcription factor [59]. Upregulation of PPARα expression after GLP1 receptor stimulation inhibited the hepatic expression of lipogenesis enzymes, such as acetyl-CoA carboxylase, whereas it promoted the hepatic expression of enzymes related to fatty acid oxidation, such as carnitine palmitoyltransferase I [59]. Likewise, it was observed that GLP1 receptor stimulation by exenatide in the rat model of high-fructose diet-induced NAFLD can downregulate the expression of sterol regulatory element-binding protein-1 (SREBP-1), a key transcription factor promoting the expression of genes involved in de novo lipogenesis and glycolysis [60]. Downregulation of SREBP-1 by exenatide markedly suppressed the expression of lipogenesis-related enzymes, such as stearoyl CoA desaturase 1, acetyl-CoA carboxylase, and fatty acid synthase, and ameliorate hepatic steatosis [60]. Consistently, a recent meta-analysis of 8 clinical trials with 2413 patients indicated that 24 weeks of treatment with semaglutide markedly reduced the serum levels of aspartate transaminase and alanine transaminase and significantly decreased liver fat content and stiffness in patients with NAFLD or NASH [61].

By developing dual or even triple agonists, such as tirzepatide and retatrutide that, in addition to GLP1, can target other receptors, such as GIP and glucagon receptor, we witnessed greater success in the management of obesity in recent years [20] [62]. Such promising results illuminate that targeted therapy for specific mechanisms that are involved in disease pathogenesis can result in unprecedented breakthroughs in clinical outcomes. However, more trials are still needed to verify the benefits of such drugs for atherosclerotic cardiovascular diseases and NAFLD.

Mitochondrial dysfunction and oxidative stress

NAFLD is associated with perturbation of mitochondrial function, which leads to oxidative stress, inflammation, and hepatic accumulation of fatty acids [63] [64]. All measures of mitochondrial function, including basal respiration, ATP-linked respiration, maximal respiration, and reserve capacity, are markedly reduced in advanced NAFLD compared with mild to moderate NAFLD [63]. Impaired mitochondrial function increases the release of numerous inflammatory cytokines such as interleukin 6 (IL6), interleukin 8 (IL8), and tumor necrosis factor α (TNF-α) and induces a proinflammatory state [63]. Mitochondrial dysfunction leads to ineffective fatty acid oxidation in NAFLD and precedes insulin resistance [65]. Besides, mitochondrial dysfunction worsens with NAFLD progression [65]. Recently, it was shown that downregulation of specific genes related to mitochondrial respiration, such as Pklr and Chchd6, can shift hepatocytes’ energy production from mitochondrial respiration toward glycolytic metabolism and significantly improve liver steatosis [66]. On the contrary, improvement of mitochondrial respiration has been associated with the resolution of liver steatosis in the rat model [67]. Improving mitochondrial function through the enhanced function of peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α) and transcription factor A (TFAM) can modulate liver steatosis [68]. Similar to liver steatosis, obesity is associated with mitochondrial dysfunction [68].

Mitochondrial dysfunction is also deeply involved in the pathogenesis of cardiovascular diseases [69] [70]. Mitochondrial dysfunction, oxidative stress, and insufficient production of ATP are the cornerstones of heart failure [69]. Maintenance of mitochondrial membrane potential and restoration of mitochondrial respiration can effectively alleviate heart failure [71]. Furthermore, mitochondrial dysfunction-related inflammation facilitates the progression of atherosclerotic cardiovascular diseases [72]. Furthermore, efficient mitochondrial function can alleviate myocardial injury in myocardial infarction [73]. Improvement in mitochondrial biogenesis through upregulation of the PGC-1α-nuclear respiratory factor 1 (NRF1)-TFAM signaling pathway can ameliorate endothelial dysfunction [74].

Mitochondrial dysfunction is similarly involved in obesity, NAFLD, and atherosclerotic cardiovascular diseases and aggravates endothelial dysfunction, inflammation, and insulin resistance.

Inflammation

Inflammation is an inseparable component of metabolic syndrome and metabolic diseases, participating in the development and progression of cardiovascular diseases, diabetes, and NAFLD [75] [76]. By activating the pro-inflammatory immune response, obesity particularly induces a chronic low-grade inflammatory response, which can damage functional cells of different tissues in the long term and interfere with the normal function of different organs [75]. Compared with individuals with normal BMI, individuals with overweight, obesity, or morbid obesity have markedly higher white blood cell counts and serum CRP and erythrocyte sedimentation rate (ESR) [76]. Similarly, it was found that compared with children with normal BMI, children with obesity have higher counts of lymphocytes, leukocytes, and platelets and elevated serum levels of leptin and inflammatory cytokines, such as IL6 and TNF-α [77]. Interestingly, Alzamil et al. reported that obese diabetic patients have significantly higher serum levels of TNF-α compared with non-obese diabetic patients, and TNF-α level significantly and positively correlates with the serum HbA1c level and insulin resistance, suggesting the importance of the chronic low-grade inflammation in metabolic syndrome [78]. Using data from 10 181 participants from Northern Taiwan, Yu et al. reported that mild or moderate-to-severe fatty liver independently predicted higher levels of hs-CRP and fibrinogen, and cardiovascular risk score was significantly associated with the coexistence of fatty liver and high levels of hs-CRP and fibrinogen [79]. Lund et al. observed that a more severe low-grade inflammation, measured by fasting serum high-sensitivity CRP (hsCRP) level, independently predicts a greater cardiometabolic risk, and more severe dyslipidemia, insulin resistance, and hepatic steatosis in children with obesity or overweight [80]. Besides, a meta-analysis of 91 studies with 435 007 participants indicated that metabolically unhealthy obese individuals have higher serum levels of CRP and IL6 than metabolically healthy obese individuals [81].

Interestingly, Fuchs et al. observed that the abundance of proinflammatory macrophages and CD4+++and CD8+++T-cell and the expression of several proinflammatory cytokines were higher in the subcutaneous abdominal adipose tissue of obese patients with NAFLD, compared with lean individuals or obese patients without NAFLD [82]. Similarly, a meta-analysis of 51 studies with 36074 patients comprising NAFLD and 47052 healthy subjects indicated that high levels of circulating CRP, IL1β, IL6, TNF-α, and intercellular adhesion molecule-1 (ICAM-1) are associated with increased risk of NAFLD [83]. These findings suggest that the presence of NAFLD can intensify the proinflammatory state induced by obesity and further increase the risk of atherosclerotic cardiovascular diseases [82]. Moreover, it was previously uncovered that the serum level of hsCRP increases with the increase in the number of metabolic conditions, such as obesity, NAFLD, and atherosclerotic cardiovascular disease, suggesting inflammation as a common pathophysiologic mechanism involved in all of these metabolic conditions [84].

Obesity promotes the nuclear translocation of nuclear factor κB (NF-κB), a major transcription factor for many inflammatory cytokines, and activates several key molecules in inflammatory signaling pathways, such as mitogen-activated protein kinases (MAPK) and Jun N-terminal kinase (JNK) [85]. In particular, it was observed that conditioned medium from obese adipose tissue activated toll-like receptor 4 (TLR4), a pattern recognition receptor on the cell surface, thereby promoting nuclear translocation of NF-κB and enhancing NF-κB-mediated expression of inflammatory cytokines such as IL6, TNF-α, and IL1β [86]. In line with these findings, Kim et al. found that simulation of TLR2 and TLR4 receptors and activation of the systemic inflammatory response in rabbits receiving a high-cholesterol diet accelerated the progression of both atherosclerotic cardiovascular disease and NAFLD, illuminating the importance of the chronic inflammatory response in the progression of cardiovascular disease and NAFLD in obese individuals [87]. On the other hand, it was found that inhibiting these signaling pathways and suppressing obesity-associated inflammation can ameliorate atherosclerosis, myocardial infarction, and cardiomyopathy in animal models [88] [89] [90]. Similarly, inhibition of NF-κB-mediated inflammatory response was shown to ameliorate myocardial injury in the mice model of NASH [91].

Gut dysbiosis

Recently, an increasing number of studies have shed light on the importance of gut microbiota in obesity and its metabolic complications, such as diabetes and NAFLD [92]. Analysis of stool samples from 20 monozygotic Korean twins uncovered that there are specific alterations in both the composition and function of gut microbiota, even in the early phase of developing obesity and diabetes [93]. Kravetz et al. showed that obese youth with NAFLD have an increased Firmicutes to Bacteroidetes ratio and decreased abundance of Bacteroidetes, Prevotella, Gemmiger, and Oscillospira, compared with those without NAFLD [94]. Inoculation of Firmicutes and Bacteroidetes from healthy subjects into germ-free mice revealed that Firmicutes induces weight gain and intrahepatic lipogenesis, compared with Bacteroidetes [95]. The analysis of fecal samples from 1148 individuals showed that patients with NAFLD have a reduced abundance of Ruminococcaceae and the genus Faecalibacterium [96]. Furthermore, patients with coronary heart disease had a significantly lower abundance of Parabacteroides and Collinsella in their feces [97]. However, the coincidence of NAFLD and coronary heart disease was associated with an increased abundance of Copococcus and Veillonella [97]. Gut microbiota can release certain substances capable of activating or deactivating particular receptors or signaling pathways that are involved in the regulation of satiety or metabolism [98]. Using these products, gut microbiota can partly rearrange brain function far from the central nervous system [98]. Gut-derived endotoxins have been implicated in the pro-inflammatory response caused by hepatic macrophages [99]. Furthermore, the products of gut microbiota can directly affect metabolic health. For instance, short-chain fatty acids and butyrate generated by gut microbes play a crucial role in preventing obesity and improving NAFLD and insulin resistance [92] [100].

It was illuminated that patients with HFpEF have a lower abundance of short-chain fatty acid-producing microbiota in their intestines [101]. Also, patients with severe congestive heart failure had a significantly diminished abundance of phylum Firmicutes and several short-chain fatty acid-producing bacteria compared with healthy controls [102]. Short-chain fatty acids improve endothelial dysfunction, attenuate inflammation, decrease vascular tonicity, and prevent left ventricular hypertrophy and fibrosis [103]. Interestingly, gut microbiota transfer from lean subjects led to a significantly improved insulin sensitivity in individuals with metabolic syndrome, with a notable increase in butyrate-producing species [100]. Also, it was found that patients with NAFLD have higher serum levels of N,N,N-trimethyl-5-aminovaleric acid (TMAVA), which is mainly a metabolite of Enterococcus faecalis and Pseudomonas aeruginosa [104] . Giving TMAVA to normal mice contributed to the development of NAFLD, which was associated with decreased carnitine synthesis and diminished mitochondrial fatty acid oxidation [104].

Organ et al. revealed that inhibition of trimethylamine N-oxide (TMAO) synthesis by gut microbiota can improve left ventricular remodeling and function in the mice model of aortic constriction model [105]. Similarly, it was found that compared with human healthy microbiota transfer, microbiota transfer from patients with NAFLD to high-fructose, high-fat diet-fed mice leads to higher hepatic triglycerides and plasma LDL-C levels [106]. Rodriguez et al. indicated that an increased population of Akkermansia and Butyricicoccus and a decreased population of Anaerostipes enhance the effect of inulin in decreasing body weight and liver fat content in high-fat diet-fed mice [107].

The anti-obesity property of resveratrol is associated with increased intestinal population of certain gut microbes such as Bacteroides, Lachnospiraceae_NK4A136_group, Blautia, Lachnoclostridium, Parabacteroides, and Ruminiclostridium_9 in mice [107]. Interestingly, Wang et al. revealed that transplantation of these germs to high-fat diet-fed mice ameliorates their weight gain, suppresses inflammation, and modifies hyperlipidemia [108].

Bariatric surgeries also modulate gut microbial composition [109] [110]. For instance, it was shown that sleeve gastrectomy increases Clostridium species abundance, Roux-en-Y gastric bypass increases the abundance of Escherichia coli, Streptococcus and Veillonella, and both of them increase Akkermansia muciniphila population [109]. Previously, it was shown that diet modification and physical activity are associated with the rearrangement of gut microbiota in patients with NAFLD [111]. Surprisingly, the meta-analysis of 21 randomized clinical trials with 1252 participants indicated that the use of probiotics can contribute to weight loss, decrease alanine aminotransferase, and improve liver stiffness and hepatic steatosis in NAFLD [112].

Taken together, an increasing number of studies are indicating that gut dysbiosis has certain involvements in the metabolic syndrome and its complications; however, the exact role of different species and their function on the metabolism remains to be known.

RAAS overactivity

Obesity activates RAAS by upregulating angiotensinogen, angiotensin 1, and angiotensin-converting enzyme (ACE) [113]. Stimulation of angiotensin II receptor 1 by angiotensin II or soluble (pro)renin receptor leads to endothelial dysfunction and arterial stiffness and contributes to developing hypertension in obesity [114]. Angiotensin receptor 1 is locally overexpressed in the subcutaneous adipose tissue of patients with obesity and hypertension [115]. Engeli et al. revealed that obese women have increased circulating angiotensinogen, renin, aldosterone, and angiotensin-converting enzyme compared with lean women [116]. Angiotensin II leads to greater vasoconstriction in the arterioles of visceral adipose tissue in patients with hypertension and obesity compared with patients with obesity and normal blood pressure [117]. Furthermore, it was found that 5% weight loss is associated with 27% reduction in angiotensinogen levels, 43% reduction in renin, 31% decrease in aldosterone, 12% decrease in ACE activity, and 20% decrease in angiotensinogen expression in the adipose tissue [116]. Consistently, it has been observed that decreased arterial stiffness and blood pressure after bariatric surgery is associated with a significant reduction in plasma renin activity and plasma aldosterone [118] [119].

Interestingly, Yoneda et al. uncovered that particular polymorphisms of the ATGR1 gene can enhance the incidence of NAFLD or the risk of fibrosis in NAFLD [120]. Consistently, it was found that the use of RAAS inhibitor is associated with decreased fibrosis stage in patients with NAFLD [121]. In addition, the analysis of data from 96 inpatients unveiled that serum angiotensin II level is independently and positively associated with a slightly increased risk of NAFLD [122]. Previously, it was shown that RAAS inhibitors can ameliorate liver steatosis and fibrosis in animal models, but it was not sufficiently supported by human studies [123] [124]. Also, animal studies have shown that RAAS inhibition can partly improve insulin resistance and improve impaired glucose metabolism [125] [126]. Importantly, Kim et al. found that, however, RAAS inhibitors cannot prevent the development or progression of NAFLD in the general population, they are protective against NAFLD in individuals with BMI+≥+25 kg/m² or fasting plasma glucose (FPG)+<+100 mg/ml [127]. RAAS inhibitors decreased the incidence [BMI+≥+25 kg/m²: OR 0.708 (0.535–0.937), FPG of+<+100 mg/ml: OR 0.774 (0.606–0.987)] and progression [BMI+≥+25 kg/m²: OR 0.668 (0.568–0.784), FPG of+<+100 mg/ml: OR 0.732 (0.582–0.921)] of NAFLD among these groups of patients [127]. Elevated levels of lipids in the circulation have been associated with higher angiotensin II levels and renin activity in the livers of high-fat-diet-fed apolipoprotein E knockout mice [128]. Also, cholesterol loading upregulated renin activity and angiotensin II expression in the HepG2 cells. In addition, cholesterol loading augmented the synthesis of extracellular matrix components such as fibronectin, α smooth muscle actin, and collagen type I, which was positively correlated with RAAS overactivity [128]. In return, angiotensin II treatment promoted the expression of sterol regulatory element-binding protein (SREBP) 2, SREBP cleavage activating protein (SCAP), and LDL receptor and resulted in intrahepatic lipid accumulation both in vivo and in vitro [128]. Moreover, angiotensin II receptor 1 gene knockout in mice or its inhibition in HepG2 cells by telmisartan significantly attenuated LDL receptor pathway [128]. Despite the positive effect of the ACE/AngII/AT1R axis on intrahepatic lipid deposit, the ACE-2/angiotensin 1–7/Mas axis was shown to protect against NAFLD in mice [129] [130]. ACE-2 activation mitigates endoplasmic reticulum stress, ameliorates mitochondrial dysfunction, alleviates liver inflammation, downregulates the expression of lipogenic enzymes, and reduces triglyceride accumulation [130] [131] [132]. These findings suggest that there is a bidirectional connection between RAAS and intrahepatic lipid metabolism. RAAS can serve as a contributory factor for intrahepatic lipid accumulation. In addition, it has been reported that treatment with ACE inhibitors can greatly decrease the risk of liver cancer, cirrhosis complications, and liver-related events in patients with NAFLD [133].

RAAS function is associated with a wide variety of cardiovascular diseases, such as hypertension, atherosclerosis, heart failure, myocardial infarction, and stroke [134] [135] [136]. Treatment with ACE inhibitors reduces all-cause and cardiovascular mortality in patients with heart failure [134]. Similarly, RAAS inhibition has been associated with a significant reduction in all-cause and cardiovascular mortality among patients with hypertension [135]. Interestingly, ACE inhibitors and angiotensin receptor blockers (ARBs) can cause 11% decrease in the composite outcome of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke [136]. ACE inhibitors and ARBs improve the risk of mortality among survivors of myocardial infarction and significantly lower the 3-year risk for myocardial infarction among them [137]. A 12-month follow-up of 15 073 patients with acute myocardial infarction revealed that the use of ACE inhibitors and ARBs significantly lowers all-cause mortality and hospitalization for heart failure [138]. RAAS overactivity can stimulate pathologic cardiac remodeling through several mechanisms, such as promoting fibroblast growth factor 23 (FGF23), extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (p38-MAPK), and transforming growth factor β (TGF-β) signaling pathways [139] [140] [141] [142] [143]. Angiotensin II overactivity stimulates endothelial dysfunction, vascular fibrosis, and remodeling, resulting in atherosclerosis, and hypertension [144].

All in all, obesity enhances RAAS function, which can contribute to the development and progression of NAFLD. In return, hepatic steatosis strengthens RAAS function; hence, a futile cycle begins. Finally, the augmented function of RAAS in obesity, NAFLD, or their coincidence advances to cardiovascular diseases ([Fig. 1]).

Fig. 1 Implication of RAAS overactivity in the cardiometabolic effect of obesity. Patients with obesity have some degrees of RAAS overactivity. Increased levels of renin, angiotensinogen, ACE, and upregulation of angiotensin receptor type 1 can promote the expression of SCAP, SREBP2, and lipogenic enzymes in the liver, leading to dyslipidemia and NAFLD. In return, higher cholesterol levels can stimulate RAAS overactivity. Finally, overactivation of RAAS and increased lipogenesis leads to NAFLD and a wide variety of cardiovascular conditions, including atherosclerosis, hypertension, myocardial infarction, stroke, and heart failure.

Endothelial dysfunction

Obesity is associated with the uncontrolled release of reactive oxygen species, numerous inflammatory cytokines such as IL6, ILβ, TNF-α, and monocyte chemoattractant protein-1 (MCP-1) that can lead to endothelial dysfunction and stimulate atherogenesis and thromboembolism [145] [146]. Uncontrolled oxidative stress resulted in endothelial nitric oxide (eNOS) uncoupling and impairs nitric oxide release and vasodilation in obese rats [147]. Obesity is also associated with the release of an excessive amount of leptin from adipocytes [148]. Leptin stimulates leptin receptor in the adrenal gland and promotes aldosterone secretion, which can help salt and water retention [148]. Obesity stimulates leptin-mediated activation of aldosterone-dependent hypertension and endothelial dysfunction [149]. Obesity also leads to vascular hyperresponsiveness to angiotensin II and increases the release of potent vasoconstrictors such as endothelin 1 [150] [151]. Moreover, patients with obesity have decreased response to vasodilator agents [152]. Interestingly, bariatric surgery reduces the plasma levels of endothelin 1 in patients with obesity [153]. A combination of several mechanisms seems to be involved in the pathogenesis of endothelial dysfunction in obesity.

Narayan et al. have shown that compared with the control group, patients with NAFLD without metabolic syndrome have a lower flow-mediated dilatation (FMD), measured by brachial artery Doppler ultrasound [154]. Similarly, measuring the flow-mediated dilatation (FMD) of the brachial artery of 139 patients without diabetes and hypertension showed that FMD (OR+=+0.85, p+=+0.035) and high triglycerides (OR+=+76.4, p+=+0.009) were significantly and independently associated with steatohepatitis in liver biopsy [155]. Importantly, it was shown that higher degrees of steatosis are associated with more severe endothelial dysfunction based on FMD [156]. For instance, patients with NASH have significantly lower (standardized mean difference of –0.81, 95% CI –1.51 to –0.31) FMD compared with those with pure steatosis [157].

Endothelial dysfunction is deeply involved in the pathogenesis of a wide variety of cardiovascular diseases, including hypertension, ischemic heart disease, stroke, peripheral artery disease, and heart failure [158]. Decreased levels of vasodilators such as nitric oxide and increased levels of vasoconstrictors such as endothelin 1, as well as uncontrolled endothelial oxidative damage, can greatly increase the risk of cardiovascular diseases [159]. The meta-analysis of 32 studies with 15 191 participants unveiled that 1% increase in brachial FMD independently and significantly predicts a lower risk of cardiovascular events and all-cause mortality (pooled RR 0.90, 95% CI 0.88–0.92) [160]. The study also found that 0.1 increase in reactive hyperemia index significantly protects against cardiovascular events and all-cause mortality (pooled RR 0.85, 95% CI 0.78–0.93) [160]. Similarly, another meta-analysis consisting of 14 753 individuals uncovered that individuals with high FMD experience a significantly decreased pooled overall cardiovascular disease risk (pooled RR 0.49, 95% CI 0.39–0.62) compared with those with low FMD [161].

Endothelial dysfunction not only increases cardiovascular risk but also is involved in the pathogenesis of NAFLD [162]. Herein, Furuta et al. showed that vascular cell adhesion molecule 1 (VCAM1) is upregulated in high-fat diet-induced NASH murine liver sinusoidal endothelial cells [162]. A similar pattern of VCAM1 expression was observed in human NASH. Inhibition of the mitogen-activated protein 3 kinase (MAP3K) mixed lineage kinase 3 (MLK3), VCAM1 neutralizing antibody, VCAM1 pharmacological inhibition, or VCAM1 knockout significantly protected against NASH and liver fibrosis, mainly via reducing the hepatic abundance of proinflammatory monocytes [162]. Likewise, Guo et al. have shown that under a lipotoxic condition, hepatocytes present active integrin β1-enriched extracellular vesicle that facilitates monocyte infiltration of the liver [163]. The inflammatory response caused by macrophages plays a major role in the development and progression of NAFLD [99]. Treatment with integrin β1 antibody markedly protected against liver inflammation and prevented liver fibrosis [163]. Endothelial dysfunction precedes inflammation and fibrosis in NAFLD [164]. Feeding rats with a high-fat diet showed that animals had reduced AKT-mediated eNOS phosphorylation, decreased eNOS function, and diminished endothelium-dependent vasodilation, even before the establishment of liver inflammation and fibrosis [164]. Compared with wild-type mice, eNOS-knockout mice had more severe hepatic lipid accumulation and inflammation after receiving high-fat diet [165]. Likewise, Persico et al. observed that patients with NAFLD suffer from eNOS dysfunction [166]. eNOS deletion was associated with impaired mitochondrial biogenesis, autophagy, and mitophagy, diminished fatty acid oxidation capacity, and more severe inflammation and fibrosis in mice fed with Western diet [167]. Furthermore, eNOS deletion partly prevents the activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a master antioxidant molecule, in NAFLD [167].

NAFLD is associated with the upregulation of endothelin 1, which contributes to NAFLD progression and liver fibrosis [168]. Consistently, ambrisentan, an endothelin 1 receptor antagonist, markedly prevented liver fibrosis in a mice model of NAFLD [169]. Furthermore, the development of NAFLD has been associated with higher hepatic expression of E-selectin and plasma levels of E-selectin in the mice model of Western diet-induced NAFLD [170]. E-selectin is a biomarker of endothelial dysfunction and mediates inflammatory cell adhesion and tissue infiltration [171]. Consistently, improving endothelial function by CU06-1004 ameliorated endothelial dysfunction by decreasing hyperpermeability and inflammation, attenuated hepatic steatosis, inflammation, fibrosis, and liver sinusoidal epithelial cells capillarization in the mice model of NAFLD/NASH [172].

Endothelial dysfunction is a common language in obesity, NAFLD, and atherosclerotic cardiovascular diseases. Obesity is associated with endothelial dysfunction, and NAFLD aggravates it, ending in unfavorable cardiovascular outcomes and progression of NAFLD/NASH ([Fig. 2]).

Fig. 2 The implication of endothelial dysfunction in the pathogenesis of obesity, NAFLD, and cardiovascular diseases. Obesity can diversely affect vascular biology and lead to perturbation of normal vascular physiology. Obesity upregulates the RAAS or induces hypersensitivity to angiotensin II. Similarly, obesity is associated with increased endothelin 1-mediated vasoconstriction and impaired eNOS-mediated vasodilation. Accumulation of visceral and subcutaneous fat also stimulates vascular and endothelial oxidative burst, and inflammatory cytokine release and leads to upregulation of adhesion molecules such as E-selectin and VCAM1. These alterations can progress to vascular remodeling, atherogenesis, and inflammatory cell infiltration. Endothelial dysfunction expedites the development and progression of NAFLD and NASH. On the other hand, NAFLD and NASH are risk factors for the aforementioned vascular and endothelial changes. Endothelial dysfunction gradually manifests as cardiovascular diseases such as ischemic heart disease, stroke, hypertension, peripheral artery disease, and heart failure.

Metabolic dysfunction-associated fatty liver disease (MAFLD)

With the increase in the number of studies unraveling the cardiometabolic complications of NAFLD, a new term, namely metabolic dysfunction-associated fatty liver disease (MAFLD), has been proposed to identify patients with fatty liver who are more likely to suffer from adverse cardiometabolic outcomes [173] [174]. Irrespective of the cause of hepatic steatosis, patients with fatty liver can be considered to have MAFLD when they have at least one of the following conditions: 1) type 2 diabetes mellitus; 2) obesity/overweight; 3) at least 2 of the following metabolic risk factors: prediabetes, increased waist circumference, blood pressure, plasma triglyceride, hs-CRP, and HOMA-IR, and decreased HDL-C [173] [174]. A huge body of evidence has shown that MAFLD exhibits a greater association with cardiovascular diseases compared with NAFLD [175] [176] [177]. A nationwide study from South Korea with 9 584 399 participants indicated that compared with patients without fatty liver, the risk of cardiovascular events was significantly higher in the NAFLD-only group (HR 1.09, 95% CI 1.03–1.15), MAFLD-only group (HR 1.43, 95% CI 1.41–1.45), and both-FLD group (HR 1.56, 95% 1.54–1.58) [178]. These studies suggest that compared with NAFLD, MAFLD is a better and stronger predictor of atherosclerotic cardiovascular events, coronary artery disease, and a higher grade of coronary artery stenosis [177]. Consistently, it was observed that compared with NAFLD, MAFLD is associated with a greater risk of central obesity, obesity, hypertension, diabetes, insulin resistance, and dyslipidemia among patients, which can explain the higher odds of atherosclerotic cardiovascular events [177] [179].

Although MAFLD is a new term adopted in the last few years, previous animal studies on fatty liver disease, such as those mentioned in this study, have extensively unraveled the pathogenesis of MAFLD rather than NAFLD. These studies mostly used diet-induced fatty liver disease models, such as high-fat diet-induced fatty liver model and high-fat and high-sugar diet-induced fatty liver model, which can simultaneously induce liver steatosis, obesity, dyslipidemia, and other components of metabolic syndrome, suggesting that despite their titles, they mostly studied the pathogenesis and treatment of MAFLD instead of NAFLD [180] [181] [182]. Furthermore, recent studies on the pathogenesis and treatment of MAFLD have employed the same methods to induce the disease [183] [184] [185]. All in all, these findings suggest that the pathophysiological mechanisms ascribed to NAFLD by previous experimental studies can be widely attributed to MAFLD and its cardiovascular sequelae as well.

Conclusion

Obesity, NAFLD, and atherosclerotic cardiovascular disease are linked by different mechanisms, such as insulin resistance, dyslipidemia, GLP1 signaling, inflammation, oxidative stress, mitochondrial dysfunction, gut dysbiosis, RAAS overactivity, and endothelial dysfunction. Obesity is often the primary driver for these molecular and cellular alterations. Obesity can increase the risk of NAFLD, and their co-existence can vigorously enhance metabolic perturbation, resulting in atherosclerotic cardiovascular disease development and progression. Weight loss approaches in combination with targeted therapy for these abnormal cellular and molecular processes may help to achieve the best outcome in metabolic syndrome.

Contributorsʼ Statement

Yunsheng Xu and Moein Ala had the idea for this article. Meng Li, Man Cui, Guoxia Li, Yueqiu Liu, and Seyed Parsa Eftekhar performed the literature search and wrote the draft. Yunsheng Xu, Seyed Parsa Eftekhar, and Moein Ala revised the article.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Publication History

Received: 15 January 2024

Accepted: 02 February 2024

Article published online:
12 March 2024