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.
