*Corresponding author: Stella M Honoré, Instituto de Biología “Dr. Francisco D. Barbieri”, Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán. Chacabuco 461, T4000ILI – San Miguel de Tucumán, Tucumán, Argentina
How to cite this article: Honoré SM, Sánchez SS. Chlorogenic Acid: A Promising Natural Agent for Non-Alcoholic Fatty Liver Disease Management. Adv Res Gastroentero Hepatol, 2021; 18(1): 555980.
Emerging and relatively consistent evidence shows that chlorogenic acid (CGA), a phenolic acid, positively modulates a variety of contributors to the non-alcoholic fatty liver (NAFLD) phenotype, through diverse and complementary mechanisms of action. Therefore, we believe that CGA is a good candidate for the management of NAFLD that deserves a review to aid future research.
As a consequence of the growing epidemics of obesity and Type 2 Diabetes Mellitus (T2DM), Nonalcoholic fatty liver disease (NAFLD) has become the most common form of chronic liver disease in the world [1-3]. NAFLD initially presents as a relatively benign, non-progressive hepatic steatosis, but can, in certain individuals, progress to a potentially serious condition . At the early stages, patients can restore liver function by changing their lifestyle (diet and exercise). However, as the disease progresses, pharmacological intervention or even a liver transplant is required . Despite NAFLD is a major public health problem, it remains difficult to treat, as there is not yet a large, validated treatment . Recent trials suggest that different approaches may be beneficial in subgroups of patients with this condition .
Flavonoids and phenolic acids have recently gained substantial attention due to their various biological and pharmacological effects . Accumulating evidence suggests that these bioactive compounds may represent a complementary and integrative natural therapy for the management of obesity and its associated disorders such as T2DM and NAFLD [7-9].
In this review, we explore the medicinal promises of chlorogenic acid (CGA) on NAFLD management based on in vitro and in vivo reported studies. This phenolic acid is able to positively modulate a variety of steps from NAFLD pathogenesis, through diverse and complementary mechanisms of action.
NAFLD is defined by the presence of steatosis in more than 5% of hepatocytes with little or no alcohol consumption [10,11]. The spectrum of the hepatic abnormalities ranging from a simple isolated steatosis to nonalcoholic steatohepatitis (NASH) characterized by steatosis along with hepatocellular injury, inflammation, and varying degrees of fibrosis  which sometimes can progress to cirrhosis and hepatocellular carcinoma .
The worldwide prevalence of NAFLD increased substantially along with increased rates of obesity and other components of the metabolic syndrome [3,5]. However, a proportion of cases have revealed a normal body mass index (BMI), a phenomenon known as “non-obese NAFLD” . In any case, the presence of T2DM in patients, displays a very high risk of developing NASH and fatty
liver associated complications, evidencing an additive detrimental
liver outcome .
It is now accepted that the metabolic and molecular changes
that lead to NAFLD results from “multiple impacts” on the liver
as a consequence of complex interactions between genetic
susceptibility, environmental factors, insulin resistance, and
changes in the gut microbiota [12,15]. In this sense, several of
the triggers of fatty liver can be traced back to events that occur
outside the liver in distant organs such as the intestine, adipose
tissue, and muscles, among others [12,16]. In this sequence of
multiple events, metabolic alterations in lipid homeostasis (free
fatty acids, non-HDL-cholesterol) have been reported to precede
fatty liver onset . This initial impact results in the development
of macrovesicular steatosis with an accumulation of liver fat .
Insulin resistance (IR) plays a key role in the development
and progression of steatosis / NASH, promoting de novo hepatic
lipogenesis and failing to suppress adipose tissue lipolysis, with
the consequent rise of fatty acids in the liver . In an attempt to
compensate for these changes, both hepatic fatty acid β-oxidation
and VLDL secretion are initially upregulated. However, this is
insufficient to decrease the continuous flow of fatty acids to the
liver that leads to tissue injury . In some patients, steatosis even
worsens IR by engaging in a vicious cycle once NAFLD develops.
The cytokines derived from the dysfunctional adipose tissue, the
free fatty acid-induced ectopic fat deposition, and lipotoxicity
increase insulin resistance with the consequent changes in glucose
and lipid metabolism . The accumulation of fat in the liver,
specifically in the form of triglycerides, impacts the production of reactive oxygen species and endoplasmic reticulum stress along
with mitochondrial dysfunction . Excess nutrients overwhelm
the endoplasmic reticulum (ER), which activates the unfolded
protein response and triggers the development of IR through
various mechanisms, including activation and inflammation of
c-jun kinase N-terminal (JNKs) . Oxidative stress can promote
lipid peroxidation in the hepatocytes and induce the secretion of
pro-inflammatory cytokines and the activation of stellate cells
through multiple signaling pathways, which in turn lead to fibrosis
In recent years, a crosstalk between the gut microbiota and
multiple organs of the host has been demonstrated with a beneficial
role in physiological regulation . Nevertheless, changes in
the microbiota composition are recognized as key players in the
pathogenesis of NAFLD . The intestinal microbiota not only
influences the absorption and elimination of nutrients to reach
the liver. It also induces changes in the liver microenvironment
by supplying gut-derived factors that stimulate hepatocytes to
release free oxygen radicals and inflammatory cytokines that
activate downstream signaling pathways such as nuclear factor
Chlorogenic acid (CGA) also known as 5-O-caffeoylquinic acid
(5-CQA) (IUPAC numbering) or 3-CQA (pre-IUPAC numbering)
(Figure 1) , is one of the most abundant isomers of
caffeoylquinic acid in nature. It is produced by the esterification of
caffeic acid and L-quinic acid in certain plant species, in response
to environmental stress .
CGA can be found in varying amounts in seeds, leaves, fruits,
roots, and tubers forming part of the human diet [7,28-30].
Substantial amounts of CGA have been reported to be available in
green tea and coffee extracts  and lower in apples, blueberries,
strawberries, tomatoes, and potatoes . Chlorogenic acid is also
present in dairy products, as part of the phenolic content of milk
influenced by animal grazing .
As a natural plant extract from a wide range of sources, CGA
exhibits many biological properties including antioxidant, antiinflammatory,
antimutagenic, anticancer, immunomodulatory,
antibacterial, antiviral, particularly hypoglycemic and
hypolipidemic effects . Recently, the functions and applications
of CGA, in relation to liver metabolism, have been highlighted in
both the biological and medical fields [9,33].
Several lines of evidence indicate that CGA could play vital
roles in regulating metabolic dysfunction closely associated with
the onset and progression of NAFLD [33,34].
Impact 1: Improvement of lipid metabolism:
The enhancement of de novo lipogenesis, suppression of β-oxidation,
and decreased lipid export from the liver are the major reasons for
the promotion of fat accumulation in the liver [18,35]. Recently,
Zamani-Garmsiri  using a NAFLD rodent model found that CGA
alone or in combination with metformin attenuates the expression
of the lipogenic genes SREBP-1c and FAS. CGA also induces the
expression and strengthens the activity of CPT-1, a fatty acid
oxidation speed limit enzyme, and promotes the oxidation of fatty
acid. A consequent decrease in plasma and triglyceride liver levels
was achieved, demonstrating the antilipidemic function of CGA in
HFD-fed mice. In addition, Ma et al.  have shown that CGA is
able to reduce the transport of long-chain fatty acids into the liver
by inhibiting the diet-induced expression of PPARγ and its target
genes CD36 and Fabp4. Also, CGA drastically reduces the level
of Mgat1 mRNA, shown to be involved in triglyceride synthesis
. In addition to the effect on PPARγ, other studies have shown
that CGA could enhance PPARα levels in the liver and stimulate
lipid utilization through adiponectin receptor-mediated signaling
pathway [39-41]. It was also suggested that the effects of CGA
could be linked to the modulation of cholesterol metabolism .
Some in vitro evidence indicates that CGA may indirectly decrease
lipid accumulation in the liver by effectively inhibiting HMG-CoA
by reducing cholesterol synthesis .
Impact 2: Improvement of oxidative status:
The appearance and persistence of oxidative stress in the liver seem to play a
fundamental role in the development of inflammation and NAFLD
progression to more severe stages . In fact, higher production
of oxygen and nitrogen radical species, a lack of endogenous
antioxidant defenses, and mitochondrial structural defects within
hepatocytes were observed in patients with NASH . So,
targeting oxidative stress and inflammation could represent one
of the main pathways of innovative NAFLD therapies .
Several studies in vivo and in vitro have found that plant
extracts containing CGA have anti-inflammatory and antioxidant
activities [45-48]. It has been shown that CGA up-regulates cellular
antioxidant enzymes and suppresses ROS-mediated NF-κB, AP-
1, and MAPK activation in vitro . Also, CGA could promote
scavenge free radical, up-regulate the expression and stimulate antioxidant enzymatic activities of SOD and GPx, CAT to attenuate
NAFLD in vivo [47,49]. Additionally, Budryn et al.  showed a
high reduced to oxidized glutathione (GSH/GSSG) ratio in the liver
and a high concentration of the antioxidants in blood serum, as a
result of the consumption of diets containing microencapsulated
Impact 3: Improvement of inflammation:
Abnormal lipid accumulation in hepatocytes increases oxidative stress and leads to
lipotoxicity, which triggers liver inflammation . The secretion
of pro-inflammatory cytokines in the hepatocytes is accompanied
by macrophage infiltration and a change in macrophage
phenotype M2 (anti-inflammatory) to M1 (pro-inflammatory) in
the infiltrated tissues, key players in the metabolic inflammation
observed in NAFLD . CGA reduces the transcription of TNF-α,
IL-6, MCP-1, and CRR2, suppressing the NF-κB activity, reducing
inflammatory responses in the liver of HFD mice [37,38]. The
modulating action of CGA on the NF-kB signaling was previously
demonstrated by  in a lipopolysaccharide (LPS)-challenge
in mice. In addition, CGA also could reverse the HFD-induced
activation of TLR4 signaling pathway in liver  and decrease
macrophage marker genes (including F4/80, CD68, CD11b and
CD11c) and pro-inflammatory mediator genes (MCP-1 and TNF-α)
in the liver and adipose tissues . Recently, it was determined
that CGA is capable of suppressing inflammation by inhibiting the
activation of TLR4 / sphingosine (SPK / S1P), highlighting the role
of CGA in preventing progression to NASH .
Impact 4: Improvement of insulin sensitivity:
Insulin resistance is at the core of the pathophysiology of metabolic
syndrome and T2DM. CGA is able to exert vital roles in the regulation
of metabolic abnormalities closely associated with the occurrence
and progression of NAFLD . Accumulating evidence suggests
that CGA may improve adipose tissue dysfunction and in turn
reduce the development of obesity-linked IR [6,53]. According
to Ma et al. , CGA is able to sensitize peripheral tissues for
insulin response by attenuating inflammatory phenotypes in both
adipose and liver tissues of obese mice.
On the other hand, hepatic IR is known to be associated with
dysregulated glucose metabolism, as a consequence of an increase
in gluconeogenesis and a reduction in glycogen synthesis. Recent
findings showed that AMP-activated protein kinase (AMPK)
plays a major role in the control of hepatic metabolism .
AMPK activation in the liver has metabolic consequences on
lipids and glucose due to its ability to integrate nutritional and
hormonal signals . CGA has been shown to regulate glucose
overproduction by inhibiting glucose-6-phosphatase (G-6-Pass)
activity through AMPK stimulation . Meanwhile, by specific
binding to AKT, CGA is able to promote glucose uptake in liver
cells by stimulating glycogen synthesis through phosphorylation
of molecules downstream of GSK3β / FOXO1 signaling . In
addition, the increased expression and translocation of glucose
transporter type-4 (GLUT-4) in skeletal muscle mediated by AMPK activation, could also facilitate glucose clearance in peripheral
tissues, maintaining fasting glucose levels, glucose tolerance, and
insulin sensitivity [35,58]. In this way, CGA could be considered
a novel insulin sensitizer capable of maintaining glucose
homeostasis similar to metformin .
The improvement in systemic glucose control can also be
attributed to CGA inhibitory action on glucose-6-phosphate
translocase that delays absorption in the small intestine . It
was reported that CGA also inhibited the activities of 𝛼-amylase and 𝛼-glucosidase contributing to reducing the glycemic impact of food and chronically lowering blood glucose levels in patients
with T2DM at high risk of developing NAFLD [61,62].
Impact 5: Improvement of the gut–liver axis:
The gut microbiota and intestinal permeability have been demonstrated
to be the key players in the gut-liver cross-talk in NAFLD .
In NAFLD, overgrowth of the gut microbiota contributes to
the disease progression, through the leaky gut barrier .
The increased permeability allows translocation of intestinal
luminal antigens, including LPS to the liver, where they bind
to their specific CD14 and TLR4 receptors on Kupffer cells
aggravating inflammation and oxidative stress damage in the
liver . So, targeting the gut-liver axis and modulation of gut
microbiota metabolites using specific prebiotics could represent
an additional therapeutic approach for the treatment of NAFLD
. In line with this, several studies showed that CGA is able to
reverse intestinal dysbiosis, increasing the metabolic activity and/
or numbers of the beneficial Bifidobacterium spp. in both humans
and mice [39,66-68]. Simultaneously, it was found that CGA in
combination with Genistoside could enhance the intestinal barrier
function, preventing leakage of LPS derived from the intestine and
reducing plasma D-lactate in NAFLD . The reduction of gut
permeability by CGA is closely related to the restoration of the
expression of the tight junction proteins occludin, claudin-1, and
zonula occludens-1 (ZO-1) in the intestinal mucosa, together with
the inhibition of tight junction disassembly promoted by downregulation
of RhoA/ ROCK signaling .
Furthermore, the interactions between the CGA and the gut
microbiota can impact intestinal L-cell metabolism, increasing
the GLP-1 levels in the portal vein . An abnormal incretin
system has been found in nondiabetic NAFLD and NASH patients
. By binding to GLP-1R, GLP-1 could act on β-cells, through
cAMP-dependent mechanisms, helping to maintain the response
capacity of these cells to increased plasma glucose . GLP-
1 could also improve NAFLD, increasing liver lipid oxidation,
improving insulin sensitivity and inhibiting liver fat synthesis
through AMPK-activation .
Impact 6: Improvement of progression to liver fibrosis:
As seen above, oxidative and ER stresses play an important role in the
development of liver complications . NASH is characterized
by fatty liver, liver inflammation and substantial hepatocyte cell death. The activation of hepatic stellate cells (HSCs) by apoptotic
bodies, ROS, or by TGFβ from activated-kupffer cells, produces
liver collagen accumulation leading to fibrosis. In the line with
this, Shi et al.  showed that CGA could significantly improve
liver matrix remodeling reducing hydroxyproline content and
collagen Ⅰ, collagen Ⅲ, and TIMP-1 expression in CCl4-injected
rats. Moreover CGA, also prevents HSCs activation, by suppressing
PDGF/ROS generation in these cells, suggesting that the antifibrogenic
mechanisms might be related to CGA-antioxidant and
At last, it is well established that apoptotic hepatocytes
define the progression of the severity of liver disease . Thus,
limiting liver injury could be a therapeutic way to prevent the
progression of hepatic complications. Recent evidence indicates
that CGA is able to reduce oxidative stress-mediated cell death
via Nrf2 activation in HepG2 cells . Consistent with this, the
consumption of products with a high CGA content, improves
oxidative stress and reduce liver cell death constituting promising
agents for NAFLD management [27,30,46,48,75].
Based on the results obtained from various studies, we believe
that CGA, a prebiotic phenolic compound with multifunctional
properties, protects against steatosis, oxidative stress, and liver
inflammation. The combination of these health benefits makes
CGA an excellent candidate for the prevention and treatment of
NAFLD. Future research should focus both on stimulating clinical
studies on NAFLD and on analyzing the inclusion of CGA in
different matrices to ensure its bioavailability.
Aleman MN, Sánchez SS, Honoré SM (2019) Smallanthus sonchifolius roots ameliorate non-alcoholic fatty liver disease by reducing redox imbalance and hepatocyte damage in rats fed with a high fructose diet. Asian Pacific Journal of Tropical Biomedicine 2019: 365-372.
Mansour A, Mohajeri-Tehrani MR, Karimi S, Sanginabadi M, Poustchi H, Enayati S (2020) Short term effects of coffee components consumption on gut microbiota in patients with non-alcoholic fatty liver and diabetes: A pilot randomized placebo-controlled, clinical trial. EXCLI J 19: 241-250.