152 Chin J Integr Med 2012 Feb;18(2):152-160

REVIEW
Chinese Herbal Medicine in the Treatment of
Nonalcoholic Fatty Liver Disease
DONG Hui ( ), LU Fu-er (), and ZHAO Li ( )

ABSTRACT Chinese herbal medicine has developed new therapies for nonalcoholic fatty liver disease
(NAFLD) based on its unique theory system and substantial herb remedies. In this review, 21 traditional
Chinese herbs were introduced for their potential benefit in the treatment of NAFLD. Majority of them are
evaluated by experimental studies and few by multicenter clinical trials. Herbal monomers as berberine and
resveratrol, extracts from Polygonum hypoleucum Ohwi , and Artemisia sacrorum Ledeb., and formulae including
Yinchenhao Decoction (, YCHD), Qushi Huayu Decoction (, QSHYD), and Danning Tablet
() were discussed in detail on their therapeutic potentials. Most of these herbal medicines were proved to
improve biochemical and histological changes of NAFLD both in vitro and in vivo . Also, their therapeutic activities
were associated with inhibiting lipid accumulation through adenosine monophosphate-activated protein kinase
activation or upregulating low-density lipoprotein receptor (LDLR) expression, alleviating lipid peroxidation, and
reducing the production of inflammatory cytokines. Although the efficacy and safety of these herbal medicines
needed to be evaluated in multicenter large-scale clinical trials, Chinese medicine is promising and effective for
preventing and treating NAFLD disease.
KEYWORDS nonalcoholic fatty liver disease, Chinese herbal medicine

Nonalcoholic fatty liver disease (NAFLD),
characteristic as excessive fat accumulation in the
hepatocytes, is getting more and more common with
the rapid development of economy. Among more
affluent regions of China, the community prevalence
of NAFLD is approximately 15%,(1) as compared with
20%30% of the general population in North America
and other developed countries. (2,3) The present
upward trends in the obesity and type 2 diabetes
mellitus pandemic lead a further increase in NAFLD
prevalence in the immediate future.
NAFLD refers to a wide spectrum of liver disease
ranging from simple hepatic steatosis to nonalcoholic
steatohepatitis and to cirrhosis, but the patient does not
consume excessive amount of alcohol.(4,5) However,
the pathogenesis of this common liver disease has
not been better understood; until now, there has been
no specific or effective treatment. Chinese medicine
(CM) is an excellent alternative and complementary
medicine in treating NAFLD. NAFLD is referred as
Gan-Pi () disease on CM, which is a consequence
of overintake of greasy food, sedentary lifestyle, and
emotional upset. The CM pathogenesis of NAFLD
is internal retention of phlegm and dampness, blood
stasis, Liver qi stagnation, and the deficiency of
Spleen (Pi) or Kidney (Shen). Moreover, the strategy
in the treatment of NAFLD focuses on strengthening
the function of Spleen and Kidney, relieving qi
stagnancy in the Liver, removing blood stasis, and
evacuating phlegm and dampness from the body.(6,7)
Up to now, various Chinese herbs and active
components were tested for treatment of NAFLD
(Table 1). However, the majority of them were
evaluated by experimental studies and few by
multicenter clinical trials. Therefore, the efficacy and
safety of these herbal medicines need to be evaluated
further. Most studies just showed the therapeutic
activities but did not investigate the action mechanism
intensively. In this review, we only discussed those
whom were explored deeply and intensively in detail.
HERBAL MONOMERS
CM prefers herbology, a Chinese art of
The Chinese Journal of Integrated Traditional and Western
Medicine Press and Springer-Verlag Berlin Heidelberg 2012
Supported by the National Natural Science Foundation of China
(No. 30772853, 30801492)
Institute of Integrative Traditional Chinese and Western
Medicine, Tongji Hospital, Tongji Medical College, Huazhong
University of Science and Technology, Wuhan (430030), China
Correspondence to: Prof. LU Fu-er, Tel: 86-27-83663660, E-mail:
felu@tjh.tjmu.edu.cn
DOI: 10.1007/s11655-012-0993-2
Chin J Integr Med 2012 Feb;18(2):152-160 153

Table 1. Chinese Herbal Medicine in the diabetes was associated with stimulating insulin
Treatment of NAFLD secretion and improving insulin resistant (IR).(9) Since
Monomer Herbal extract Herbal formula IR also contributes to NAFLD,(10) berberine might be
Berberine Polygonum hypoleucum Ohwi Yinchenhao Decoction potentially effective on treating NAFLD.
()
Resveratrol Artemisia sacrorum ledeb Qushi Huayu Decoction
() No exact clinical evidence supported the efficacy
Emodin Ginkgo biloba leaf Danning Tablet
()
of berberine in the treatment of NAFLD. However,
Theaflavin Schisandrae Fructus Sini Powder potential efficacy of berberine on treating NAFLD
()
was identified in experimental studies. The possible
Schisandrin B Alisma orientalis Ganzhixiao Decoction
() mechanisms may be elucidated from the following
Bifendate Hawthorn leaf flavonoids Cigu Xiaozhi Pill aspects.
()
Puerarin Fermentum Rubrum Tangzhiqing Decoction
() Berberine Activates Adenosine Monophosphate-
activated Protein Kinase
combining different medical herbs into one therapy Adenosine monophosphate-activated protein
through prescription.(8) Along with the application of kinase (AMPK) is a serine/threonine protein kinase
modern technologies in chemistry and pharmacology, that plays a central role in regulating cellular
the effective components with simplex chemical metabolism and energy balance. (11) Berberine,
structures of many Chinese herbs have been through AMPK activation, inhibits triglyceride (TG)
identified. Figure 1 showed chemical structures of and cholesterol synthesis and increases fatty acid
some herbal monomers that are potentially effective oxidation by modulating downstream-signaling
on treating NAFLD. components expression and activities, leading to the
alleviation of hepatosteatosis. Furthermore, berberine
Berberine would improve fatty liver in obese subjects, which
Berberine, an alkaloid isolated from the Chinese is probably mediated not only by peripheral AMPK
herb Coptis chinensis , has been widely used as a drug activation but also by neural signaling from the central
to treat gastrointestinal infections, such as bacteria nervous system.
diarrhea. The content of berberine in Rhizoma
Coptidis is 5.2%7.7%. In 1988, the hypoglycemic In db/db mice, berberine increased the
effect of berberine was found when berberine phosphorylation level of AMPK and acetyl-CoA
was used to treat diarrhea in diabetic patients in carboxylase (ACC) in liver. Berberine remarkably
China. Since then, berberine has been used as an elevated the expression of key fatty acid oxidation
antihyperglycemic agent by many physicians in China. genes, such as acyl-CoA oxidase (ACO), carnitine
We found that the effect of berberine on treating palmitoyltrans-ferase-1 (CPI-1), medium

Berberine Emodin Resveratrol

Theaflavin Schisandrin B Bifendate Puerarin

Figure 1. Structures of Herbal Monomers in the Treatment of NAFLD

 154
chainacyl-CoA dehydrogenase (mCAD), peroxisome
proliferator-activated receptor- coactivator-1 (PGC-
1), and uncoupling protein 2 (UCP2) in liver.(12) Berberine
also increased PPAR/ protein expression in liver
of diabetic and hyperlipidemic rats.(13) On the contrary,
berberine reduced the expressions of many lipogenic
genes including sterol regulatory element-binging
proteins-1c (SREBP-1c), peroxisome proliferator-
activated receptor- (PPAR-), ACC, stearoyl-CoA
desaturase 1 (SCD1), and fatty acid synthase (FAS).
These effects of berberine on the activation of AMPK
and fatty acid oxidation were blunted by an AMPK
inhibitor, implying that AMPK might be a player to
dissipate stored fat contents on berberine.(12)
Despite these changes, berberine did not
alter the expression of genes involved in very low-
density lipoprotein (VLDL) assembly and secretion,
such as apoB, apoE, and microsomal triglyceride
transfer protein (MTTP), precluding the possibility that
berberine might increase secretion of lipids from the
liver of obese mice. However, in high-fat-diet (HFD)-
induced NAFLD rats, berberine reversed the down-
regulated expression of the mRNA levels encoding
MTTP. In parallel, DNA methylation levels in the
MTTP promoter were elevated in the liver.(14) These
data indicated that berberine can counteract the HFD
elicited dysregulation of MTTP partially via reversing
the methylation state of its promoter, leading to
reduced hepatic fat content.
Berberine Ameliorates the Inflammatory Status
Low-grade chronic inflammation, with elevation
of inflammation markers, is hypothesized to underlie
the pathogenesis of NAFLD, possibly by inducing
insulin resistance. However, the anti-inflammatory
efficacy of berberine in the treatment of NAFLD and
diabetes is still under investigation. In an HFD and
streptozotocin-induced diabetic rat model, no effect
of berberine was observed on the plasma levels of
inflammatory cytokines, such as tumor necrosis factor-
alpha (TNF-) and C-reactive protein. Meanwhile,
berberine did not affect the state of oxidative stress
as assessed by the levels of superoxide dismutase
(SOD), malonaldehyde (MDA), and reduced
oxidized glutathione in liver. (15) However, in db/
db mice, berberine downregulated several hepatic
proinflammatory genes, including TNF-, interleukin 6
(IL-6), and serumamyloid A3 (SAA3), which proposed
to play a role in the development of steatohepatitis.(12)
Chin J Integr Med 2012 Feb;18(2):152-160
The suppression of proinflammatory responses in fatty
liver may also mediate by AMPK activation and the
transcription factor nuclear factor kappaB (NF-B)
signaling pathway.(16,17) The underlying mechanism is
still waiting for further investigation.
Berberine Up-regulates Low-density Lipoprotein
Receptor Expression
Low-density lipoprotein receptor (LDL-R) is the
primary receptor in liver for binding and internalization
of plasma-derived low-density lipoprotein-cholesterol
(LDL-C) and has a major influence on plasma and
intracellular cholesterol concentration. The mechanism
by which berberine regulating dyslipidermia is related
to the increased expression of LDL-R in both mRNA
and protein in liver. (18-20) This increase in LDLR
mRNA is a result of extended half-life of mRNA in
HepG2 cells.(19,20) Activation of extracellular signal-
regulated kinases (ERK) by berberine may contribute
to the increased mRNA stability. Moreover, the ERK
activation by berberine is specific to liver as no ERK
activation was observed in other type of cells. (21-23)
c-Jun N-terminal kinase (JNK) activation by berberine
was also reported and might be involved in the
elevation of LDLR, and this effect of berberine was
blocked by a JNK inhibitor.(24)
Furthermore, the combination of berberine
with simvastatin upregulated the LDLR mRNA in
hyperlipidemic rat livers to a level about 1.6-fold higher
than the monotherapies did. Significant reduction
of liver fat storage and improvement liver histology
were also found after the combination therapy, which
suggested their potential efficacy in the treatment of
NAFLD.(25) Figure 2 showed the possible mechanisms
of berberine in the treatment of NAFLD.
Resveratrol
Resveratrol is a polyphenolic compound present
in red grapes, Rhizoma Polygoni Cuspidati, Catsia
tora Linn, and Veratrum nigrum L. It has been shown
to be effective in preventing numerous diseases,
including cardiovascular disease, obesity, diabetes,
and cancer.(26-28) The possible mechanisms by which
resveratrol protects the liver from NAFLD may be
elucidated from the following aspects.
Resveratrol Activates AMPK
Resveratrol inhibits the expressions of many
lipogenic genes including SREBP-1, ACC, and FAS
Chin J Integr Med 2012 Feb;18(2):152-160 155

Berberine

NF-B AMPK activation ERK activation JNK activation

Inflammatory factor expression Modulate target genes expression

ADD-1, PPAR-, LDL-R RNA LDL-R mRNA

ACO, CPT-1, mCAD,
stability expression
PGC-1, UCP2 ACC, SCD1, FAS
TNF-, IL-6,
PAI-1, SAA3

Fatty acid oxidation Lipogenesis LDL-R

Hepatic inflammation Hepatic fat storage Plasma LDL-C and TG

Figure 2. Mechanisms of Berberine in the Treatment of NAFLD

Notes: (1) berberine downregulates several hepatic proinflammatory genes; (2) berberine activates AMPK and modulates
downstream-signaling components expression and activities, leading to inhibition of lipogenesis and increase of fatty acid oxidation; (3)
berberine upregulates LDL-R expression; CPT-1: carnitine palmitoyltrans-ferase-1; ADD-1: adipocyte determination and differentiation
factor-1

in liver. On the contrary, resveratrol elevated the
expression of key fatty acid oxidation genes as PGC-
1 but did not modify mitochondriogenesis and
mitochondrial activity. Most studies implicate that
AMPK activation is also involved in these effects
and AMPK is an off-target hit of resveratrol.(29,30) In
AMPK-1 or -2 deficient mice, resveratrol failed to
prevent various metabolic disorders.(31)
Resveratrol Activates Sirtuin1
Sirtuin1 (Sirt1) activation partially mediated the
effect of resveratrol on elevating ACC phosphorylation
and reducing liver fat accumulation. (32) Sirt1, a
nicotinamide adenine dinucleotide (NAD)-dependent
deacetylase, is an important regulator of energy
homeostasis in response to nutrient availability.
Hepatocyte-specific deletion of Sirt1 alters fatty
acid metabolism and results in hepatic steatosis
and inflammation. (33) In the cell model of steatosis,
resveratrol exerted the anti-lipogenic effect by
inhibiting the expression of SREBP1 via regulating
Sirt1 and forkhead box O1 (FOXO1) signaling
pathway. (34) Since resveratrol increased the NAD-
to-NADH (NAD reduced form) ratio in an AMPK-
dependent manner, resveratrol may activate Sirt1
indirectly. (31,35) Sirt1 functions as a novel upstream
regulator for liver kinase B1 (LKB1)/AMPK signaling
and plays an essential role in the regulation of
hepatocyte lipid metabolism. Targeting Sirt1/LKB1/
AMPK signaling by resveratrol may have potential
therapeutic implications for treating NAFLD.(36)
Resveratrol Ameliorates the Inflammatory Status
and Oxidative Stress
Resveratrol also improves the inflammatory status
and oxidative stress in NAFLD similar to berberine.
This therapeutic approach resulted in a decrease in
TNF- production, lipid peroxidation, and oxidative
stress. Lowered MDA levels, elevated SOD, increased
glutathione peroxidase, and catalase were also
observed in NAFLD rats treated with resveratrol.(37)
Whether resveratrol suppressing proinflammatory
responses in fatty liver by AMPK activation or NF-B,
signaling pathway is still unknown. Figure 3 showed
the possible mechanism of resveratrol in the treatment
of NAFLD.
Other herbal monomers have been
demonstrated to be effective in the treatment of
NAFLD as emodin,(38) theaflavin,(39), schisandrin B,(40)
bifendate, (41) and puerarin. (42) However, the action
mechanism is still awaiting further investigation.
Nevertheless, these agents suggest a new therapeutic
approach for preventing fatty liver progression.
HERBAL EXTRACTS
Compared with single herbs that are not often
used individually, multiple herbs are often prescribed
to form a special formula for individual condition.
Along with the application of modern technologies
 156 Chin J Integr Med 2012 Feb;18(2):152-160

Resveratrol

Lipid peroxidation Infammatory status LKB/AMPK activation Sirt1 activation

FOXO-1

SREBP-1,
SOD MDA PGC-1
TNF- ACC, FAS

Fatty acid oxidation Lipogenesis

Oxidative stress Hepatic inflammation Hepatic fat storage

Figure 3. Mechanisms of Resveratrol in the Treatment of NAFLD

Notes: (1) resveratrol ameliorates inflammatory status and oxidative stress; (2) resveratrol activates AMPK and modulates
downstream-signaling components expression and activities, leading to inhibition of lipogenesis and increase of fatty acid oxidation; (3)
resveratrol activates Sirt1 and regulating hepatic lipid metabolism via Sirt1/LKB1/AMPK or Sirt1/FOXO1 signaling pathway

in chemistry and pharmacology, the bioactivities of
many Chinese herbs have been identified. Many
scientists made an effort to purify the standard extract
of Chinese medicinal herbs with fine quality control to
enrich NAFLD therapeutic activities hopefully.
Extract of Polygonum Hypoleucum Ohwi
Polygonum hypoleucum Ohwi (EP) is a
Chinese herb that has been used for treating tumor,
arthritis, and nephritis.(43) It is reported that emodin,
catechin, epicatechin, epicatechin-3-O-gallate, and
procyanidin B2 are found in EP.(44) EP can also inhibit
ACC activity. ACC plays a crucial role in fatty acid
metabolism. A liver-specific ACC1 knockout mouse
showed less accumulation of hepatic TG when fed
a lipogenic fat-free diet, although it showed no impact
on glucose homeostasis and body fat accumulation.(45)
The inhibition of ACC1 and ACC2 expressions was
demonstrated to prevent HFD-induced nonalcoholic
fatty liver and hepatic IR. (46) EP is effective in
decreasing ACC and FAS activity, leading to
decrease of triglyceride content in HepG2 cells.(47) It
is suggested that EP might be potentially effective in
treating NAFLD.
Extract of Artemisia Sacrorum Ledeb.
Artemisia sacrorum Ledeb. (ASL) is a traditional
Chinese medicine used to treat different hepatic
diseases. Ninety-five percent ethanol eluate (EE),
an active part of ASL, could attenuate hepatic lipid
accumulation in human HepG2 cells by activating
AMPK. In addition to increasing AMPK and ACC
phosphorylation, EE down regulated the lipogenesis
gene expression of SREBP1c and its target genes,
such as FAS and SCD1, in a time- and dose-
dependent manner. On the contrary, the lipolytic gene
expressions of PPAR- and CD36 increased by EE.
These effects were abolished by pretreatment with
an AMPK inhibitor. However, EE did not affect the
gene expressions of SREBP2, LDL-R, hydroxymethyl
glutaryl CoA reductase (HMG-CoA), and glucose
transporter 2 (GLUT2). These findings indicate that
EE attenuates hepatic lipid accumulation through
AMPK activation and may be active in the prevention
of fatty liver.(48)
Other herbal extracts from Ginkgo biloba
leaf, (49) Fructus Schisandrae , (50) Hawthorn leaf, (51)
Alisma orientalis ,(52) and Fermentum Rubrum (53) are
also effective in treating NAFLD. Generally, herbal
extracts consist of a lot of known and unknown
constituents that need to be further identified. This
limits researches to explain the possible mechanisms
on treating NAFLD.
CHINESE HERBAL FORMULAE
Herbal prescriptions for NAFLD are formulated
based on the patient's predominant symptoms. Thus,
herbal formulae are mainly composed of herbs that
can remove dampness, regulate qi and blood, and
eliminate stagnation. However, it is still complex when
we collocate and combine the above three kinds
of herbs together. Though academic periodicals in
China have reported the benefits of many decoctions
Chin J Integr Med 2012 Feb;18(2):152-160
in NAFLD therapy, several problems still exist in the
recent studies. For example, the effects of decoctions
are mostly evaluated in poorly controlled clinical
trials. The efficacy of medications remains poorly
defined due to limitations of the available noninvasive
techniques used to evaluate the degree of hepatic
steatosis and inflammation in clinic. In the following,
we list some characteristic decoctions of herbs that
are promising and possibly effective in the treatment
of NAFLD.
Yinchenhao Decoction
Yinchenhao Decoction (, YCHD) is a fatty liver were 85.8%, 78.2%, 39.6%, and 34.0%,
traditional Chinese formula composed of Artemisia
capillaries Thunb, Gardenia jasminoides Ellis,
and Rheum. This prescription is used to treat liver
and gall bladder diseases for centuries. Recent
study reported the efficacy of YCHD on reducing
hepatic fat accumulation. Enhanced adiponectin
and endothelial progenitor cells and upregulation of
PPAR- might be responsible for the therapeutic
effect of YCHD in the treatment of NAFLD. In
addition, the anti-oxidative stress effect of YCHD
might be associated with the inhibition of hepatic
free fatty acid (FFA) concentrations and elevation
of the glutathione levels in hepatic tissues.
Furthermore, YCHD might promote senescence
marker protein-30 metabolism that increase
resistance to hepatic oxidative stress.(54)
Qushi Huayu Decoction
Qushi Huayu Decoction (, QSHYD) much more complex than any single herb. Under
is composed of Artemisia capillaries Thunb,
Rhizoma Polygoni Cuspidati, Hypericum japonicum
Thunb, Rhizoma Curcumae Longae , and Gardenia
jasminoides Ellis . QSHYD could effectively
reverse the elevated FFA and TG contents of the
liver tissue. Liver pathology showed that hepatic
steatosis and inflammation were improved after
intervention with QSHYD. (55) Furthermore, the
effects of QSHYD on the inhibition of fat deposition
and inflammation in liver were related with (1)
inhibiting the "FFA-Cathepsin B-phospho-inhibitor
B-TNF-" pathway of lipotoxicity; (2) affecting
the adiponectin-FFA pathway by increasing the
content of liver adiponectin receptor 2 (AdipoR2),
AMPK, carnitine palmitoyl transferase-1 (CPT-1)
concentrations and decreasing liver malony1-CoA,
ACC, and FAS concentrations; and (3) inhibiting the
fatty deposition and TNF- secretion in vitro .(56-58)
157
Danning Tablet
Danning Tablet () is a herbal formula
composed of rhubarb, griant knotweed, dried green
orange peel, and dried old orange peel. A multicenter
clinical trial was designed to evaluate the efficacy and
safety of Danning Tablet in the short-term treatment
of the patients with NAFLD. There were 232 patients
enrolled during the period of July 1999 to February
2000. They were given 35 Danning Tablets orally
three times a day for 3 months. The effective rate of
the Danning Tablet for the improvement of clinical
symptoms, serum ALT levels, blood lipid, and
respectively, after the therapy. The general mild
adverse events included diarrhea, skin rash, and
mild to moderate elevation of serum ALT level. The
incidence of adverse reaction was 15.1%. The data of
this trial indicated that Danning Tablet was effective
and safe, generally well-tolerated without severe
adverse events, in the treatment of patients with
NAFLD over a 3-month period.(59) Moreover, Danning
Tablet was an effective drug to treat the patients with
NAFLD of damp-heat syndrome type and was more
effective than ursodeoxycholic acid (UDCA).(60)
Sini Powder (),(61) Ganzhixiao Decoction
(), (62) Cigu Xiaozhi Pill (), (63)
and Tangzhiqing Decoction () (64) are
also effective on treating NAFLD. Because herbs
can interact with each other, leading to new agents
production, the constituents in herbal formula is
the condition of unclear effective constituents, it is
hard to elucidate the action mechanisms from the
view of pharmacokinetics and pharmacodynamics.
Furthermore, alterations in pharmacodynamic
interactions always manifest in the way the herb
affects a tissue or organ system either through
synergistic or antagonizing effects. Various even
undiscovered molecular targets and signaling
transduction pathways are involved in the procedure.
These interactions are generally more difficult to
predict than pharmacokinetic interactions. All of the
above retard the scientific progress of herbal formula
on treating NAFLD.
Conclusions
In this review, we introduced some Chinese
medicines that were proved to be effective in treating
NAFLD. Their efficacy was found to be associated
 158
with different mechanisms or molecular targets
including those involved in excess lipid accumulation,
lipid peroxidation, and inflammatory state. Though
most results based on experimental studies need to
be confirmed by further clinical trials, and the findings
from clinical trials also need to get more morphological
evidence, we still think that CM is promising and is
beneficial for preventing and treating NAFLD.
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(Received October 8, 2010)
Edited by CHNE Yi-yu