Ursolic acid is a phytochemical found in a wide variety of plants but most
well known for being in apple peels.
Although the science is preliminary, it seems to be able to reduce fat
accumulation and increase muscle mass gain when in a fed state, and to induce
fat burning and preserve muscle mass when in a fasted state.
Animal studies have found benefits with ursolic acid in the diet at
0.05-0.2% of the diet, which is around 10-40mg/kg (based on their weight and
food intake) and the estimated human dose equivalent to this is 1.6-6.4mg/kg
bodyweight; for a 150lb adult it would be the range of 110-440mg.
The lone human study used the higher end of this range, 150mg three times a
day with meals totalling 450mg each day, and found some biological acitivty.
Until further research arises, thrice daily dosing of 150mg with meals is
recommended.
1.1. Sources
Ursolic Acid is a pentacyclic triterpenoid that is very widely
distributed in food products and herbs.
Major sources (Food products or common supplements) include:
·
Apples (high in the peels),[1] Cranberry juices,[2] and Grape skins[3]
·
The Silphium family of plants, averaging around 1.5% dry weight[6]
·
Lantana Camara,[7]Orthosiphon aristatus,[8]
·
Common Spice herbs such as rosemary, thyme, oregano, and lavender[10] and Sage (Salvia
Officinalis)[11]
·
Gentiana striata,[12]Damnacanthus indicus,[13]Periploca forrestii,[14]Eucommia ulmoides,[15] and various other
non-supplemental herbs
2.3. Distribution
Following oral administraiton of 0.2% of the diet to rats over a
period of 11 weeks (estimated dose of 40mg/kg), Ursolic Acid can be detected in
the kidney plasma (2.83+/-0.47nmol/mg) and the kidney tissue itself
(3.51+/-0.57nmol/mg);[22] no
other organs were tested, and lower doses (0.05-0.1%) were not detected.
2.4.
Metabolism
One study that gave rats either Ursolic Acid or Oleanolic Acid
(related structure) noted that at the higher doses of both supplements that
there was a detectable serum level of the other, suggesting that
interconversion between the two exists after oral administration in rats.[22]
3.1. Artherosclerosis
Concentrations of 10uM and 30uM of ursolic acid in the drinking
water of ApoE knockout rats, over 24 weeks, can accelerate artherogenic plaque
formation.[23] These
results may not be highly extrapolatable, as ApoE knockout mice have screwed
lipid profiles already.[24]
Conversely, a low dose of Ursolic Acid (0.2% of the diet) fed to
mice with diabetes induced by streptozotocin and lacking an LDL receptor found
that ursolic acid was able to reduce by 53% the inherent lesions that occur in
the endothelium with diabetes; suggesting a protective but not necessarily
rehabilitative effect.[25] This
protective effect was more potent than resveratrol at
0.2%. Ursolic acid was also able to reduce monocyte migration to the
endothelium, which is seen as an inflammatory response (and thus, ursolic acid
in part protects via anti-inflammatory means).[25]
The discord between the two studies above[24][25] has
been investigated by a third part.[26] In
general, the two cannot be directly compared due to large differences in
methodology.
3.2. Endothelium
One study noted that, in
vitro, in human umbilical vein endothelial cells (HUVECs) as well
as cells taken from humans, ursolic acid was able to prevent cell differentiation
and induce cell death in both cell cultures potently at 12.5uM, and in isolated
cells at 6.25uM. Lower doses did not have any influence on cell death, and
3.125uM has a non-significant increase in cell differentation relative to
controls in isolated cells.[23]
4.2. Absorption
Ursolic acid, similar to structurally related pentacyclic
triterpenoids, appears to inhibit α-amylase activity although to a greater
potency than Corosolic acid or Lupeol.[35]
4.3.
Interventions
Ursolic Acid appears to beneficially influence parameters of
Diabetes when used as combination therapy alongside Rosiglitazone (anti-diabetic
drug) in mice given both concurrently.[36]
In streptozotocin-induced diabetic mice, Ursolic acid as
monotherapy note that 0.05% of the diet (approximately 10mg/kg) can reduce blood
glucose by 12.3% relative to control in 4 weeks[37] with
another study using fourfold this dose (0.2%) over a period of 11 weeks
decreased blood glucose to 53% of high-fat fed diabetic control (although still
twice that of healthy control).[25] Ursolic
acid tends to decrease blood glucose in a dose dependent manner (as some
studies have tested graded intakes of Ursolic acid within this range of
0.05-0.2%[22]) with
similar potency to Oleanolic Acid.[22]
Decreases in HbA1c have been noted with 0.05% of the diet as
Ursolic Acid in diabetic mice (9.5%), with 0.1% (19%) and 0.2% (34%; all values
relative to diabetic control) over 10 weeks, which coexisted with a reduction
in urinary glycosylated proteins and Ursolic acid being nonsignificantly less
effective than Oleanolic acid.[22]
A decrease of Aldose Reductase activity has been noted in vivo with oral
Ursolic Acid in a dose dependent manner, which at 0.2% reached 67% of diabetic
control (still 59% higher than nondiabetic control, and was not absolute
protection),[22] which
validates previous in
vitro studies noting Aldose Reductase inhibition with Ursolic
Acid in a noncompetitive manner.[38] The in vivo study also
noted minor beneficial trends in the activities of sorbitol dehydrogenase and
glyoxalase I,[22] and
anti-glycative properties have been noted to occur in hepatic tissue as well,[37] where
a beneficial trend of glucose regulatory enzymes (suppressing
glucose-6-phosphatase and upregulating glucokinase) occurs with 0.05% of the
feed .[37]
Beyond anti-glycative
protective effects, low doses of Ursolic Acid (0.01% of rat feed) have been
noted to attenuate the rate of developing diabetic nephropathy possibly
secondary to anti-inflammatory properties[39] and
less artherosclerotic lesions have been noted with Ursolic Acid, which were
slightly more protective than an equal dose (0.2% of the diet) resveratrol.[40]
5.1. Mechanisms
Upregulation of c-Cbl
associated protein (aka. CAP) protein content and mRNA has
been noted in adipocytes treated with 4-20uM Ursolic Acid.[41]
Ursolic acid at 4-20uM appears to augment Rosiglitazone-induced
glucose uptake into insulin resistance fat cells in vitro, although
combination treatment was associated with less adipocyte differentiation than
Rosiglitazone alone.[41]
Ursolic acid appears to increase lipolysis in vitro via Protein
Kinase A activation, and downstream of that Hormone Sensitive Lipase (HSL) and
Perilipin A activity.[42] Upregulation
of Adipose Tissue Lipase (ATGL) has been noted in adipocytes independent of
PKA.[42]
5.2.
Absorption
100mg/kg Ursolic Acid in rats appears to attenuate the increase
in triglycerides in response to a fatty meal, which was thought to be through
inhibiting pancreatic lipase;[43][44] an
estimated human equivalent dosage is 16mg/kg.
5.3. Interventions
10mg/kg (rat dose) Ursolic acid over 15 weeks to otherwise
healthy rats fed a high-fat diet is able to attenuate a 24% increase in body
weight to 10.7%, which is not significantly different than the active control
of 10mg/kg Sibutramine.[45] This
study noted that the high-fat induced alterations in adipokines (Ghrelin,
Leptin) and liver histology were otherwise normalized in both intervention
groups, and that Ursolic acid was associated with an increase in insulin levels
relative to high fat control and reduced glucose levels relative to all groups
including normal chow control.[45]
5.1. Mechanisms
Upregulation of c-Cbl
associated protein (aka. CAP) protein content and mRNA has
been noted in adipocytes treated with 4-20uM Ursolic Acid.[41]
Ursolic acid at 4-20uM appears to augment Rosiglitazone-induced
glucose uptake into insulin resistance fat cells in vitro, although
combination treatment was associated with less adipocyte differentiation than
Rosiglitazone alone.[41]
Ursolic acid appears to increase lipolysis in vitro via Protein
Kinase A activation, and downstream of that Hormone Sensitive Lipase (HSL) and
Perilipin A activity.[42] Upregulation
of Adipose Tissue Lipase (ATGL) has been noted in adipocytes independent of
PKA.[42]
5.2. Absorption
100mg/kg Ursolic Acid in rats appears to attenuate the increase
in triglycerides in response to a fatty meal, which was thought to be through
inhibiting pancreatic lipase;[43][44] an
estimated human equivalent dosage is 16mg/kg.
5.3. Interventions
10mg/kg (rat dose) Ursolic acid over 15 weeks to otherwise
healthy rats fed a high-fat diet is able to attenuate a 24% increase in body
weight to 10.7%, which is not significantly different than the active control
of 10mg/kg Sibutramine.[45] This
study noted that the high-fat induced alterations in adipokines (Ghrelin,
Leptin) and liver histology were otherwise normalized in both intervention
groups, and that Ursolic acid was associated with an increase in insulin levels
relative to high fat control and reduced glucose levels relative to all groups
including normal chow control.[45]
6.1. Myokines
Irisin is a myokine (although it can be secreted from other
tissues such as the brain, heart, and adipose[46]) that
is known to in part be correlated with IGF-1 kinetics, although its overall
role in skeletal muscle physiology and exercise is still being elucidated.[47][48]
Supplementation of 150mg ursolic acid three times daily with
meals (totalling 450mg daily for eight weeks) in otherwise healthy men subject
to resistance training appears to be effective in increasing serum irisin by
12% relative to placebo.[49] This
observation occurred alongside a 22.8% increase in IGF-1 relative to baseline
despite no change occurring in the placebo group given resistance training,
although eight weeks was insufficient to alter lean or fat mass significantly.[49]
6.1. Myokines
Irisin is a myokine (although it can be secreted from other
tissues such as the brain, heart, and adipose[46]) that
is known to in part be correlated with IGF-1 kinetics, although its overall
role in skeletal muscle physiology and exercise is still being elucidated.[47][48]
Supplementation of 150mg ursolic acid three times daily with
meals (totalling 450mg daily for eight weeks) in otherwise healthy men subject
to resistance training appears to be effective in increasing serum irisin by
12% relative to placebo.[49] This
observation occurred alongside a 22.8% increase in IGF-1 relative to baseline
despite no change occurring in the placebo group given resistance training,
although eight weeks was insufficient to alter lean or fat mass significantly.[49]
6.2. Mechanisms
Ursolic acid is implicated as being an agent to counter genetic
responses of fasting that mediate muscle breakdown.[34] When
fed to mice at 0.14% and 0.27% of the diet by weight (overall intake unknown)
it was able to prevent muscle breakdown via genetic signalling that is the
opposite of those that mediate muscle breakdown from fasting, and it was able
to increase skeletal muscle accrual by increasing anabolic gene transcription,
most notably that of IGF-1.[34] It
did not seem to increase IGF-1 expression in adipose tissue, suggesting that
this activity is specific to skeletal muscles. This anabolic effect has been
replicated in vitro showing
protein accrual and increasing muscle cells size, but does not influence muscle
cell differentiation.[50]
Injections of 200mg/kg bodyweight, twice a day for 7 days, was
shown in rats to reduce muscle protein loss associated with fasting.[34]
Increases in muscle protein synthesis are seen at 1uM, but
become statistically significant at 10uM.[50] It
is fairly dose-dependent of a response in increasing protein accrual, but
concentrations exceeding 25uM induce loss of protein from cells and
myotoxicity.[50] The
growth was only seen in
vitro with growth medium rather than differentiation medium or
serum-free medium, the difference being GM using 10% fetal bovine serum albumin
and DM 2% horse serum. These results suggest that ursolic acid may augment
amino acid accrual from serum amino acids, or food.[50]
Ursolic acid's influence on muscle cells appears to not
influence ribosomal content nor satellite cells, as evidence by no changes in
RNA content of muscle cells incubated with ursolic acid and no myocyte
differentation.[50]
Ursolic acid can also increase insulin-induced phosphorylation
of Akt (an intermediate in muscle protein synthesis), which is linked to muscle
protein synthesis.[51] Another
intermediate downstream of Akt and phosphorylated by S6K1/S6K2, rpS6, is only
increased under good growth conditions in
vitro but can be upregulated 1.8-fold.[50]
In rats subject to resistance training, an infusion of ursolic
acid appears to sustain the exercise-induced activation of p70S6K (downstream
of mTOR) for a more prolonged period of time than control exercise.[52]
Low dosages appear to
beneficially influence skeletal muscle, but higher dosages have been implicated
in preserving muscle mass during fasting. These higher dosages may not be
feasible due to low oral bioavailability, but lower dosages are definitely
possible. Many of the effects seen are related to the insulin-signalling
pathway of muscle anabolism. Low dosages appear to beneficially influence
skeletal muscle, but higher dosages have been implicated in preserving muscle
mass during fasting. These higher dosages may not be feasible due to low oral
bioavailability, but lower dosages are definitely possible. Many of the effects
seen are related to the insulin-signalling pathway of muscle anabolism.
9.1. Prostate
A rat model of benign prostatic hyperplasia using 5mg/kg Ursolic
acid oral administration alongside testosterone injections noted suppression of
prostatic growth to a similar degree as the active control (10mg/kg
Finasteride) and a suppression of both testosterone and DHT rivalling
Finasteride in magnitude; Finasteride was more effective in reducing serum
levels of prostate specific antigen (PSA).[57] The
authors hypothesized a 5α-reductase inhibiting effect, although it was not
established in vitro in
this study (this study was responded to,[58] which
merely discussed the need more research and product standardization).
9.2. Liver
In studies measuring liver enzymes, there is no increase
following 5mg/kg oral ingestion for 4 weeks.[57]
10.1. Angiogenesis
Ursolic acid (as well as related compounds maslinic acid and
oleanolic acid[59]) is
known as an angiogenesis inhibitor, preventing the formation of new blood
vessels from larger ones. In blood vessel cells, ursolic acid seems to act via
inhibiting the PI3K-Akt pathway and Nitric Oxide induction, which suppresses
cellular changes preceding angiogenesis.[59][60] These
results have been seen in
vivo with nontoxic dosages of ursolic acid, and ursolic acid
also inhibits expression of MMP2 and MMP9 (intermediates required for the final
stages of angiogenesis into new tissue)[61]
This inhibition of vascularization is currently under
investigation for its anti-cancer therapeutic potential, as new tumor cells
require blood flow and need angiogenesis to occur for them to survive.[62] The
previous study that tested rats with ursolic acid noted that the experimental
group having ursolic acid at 4.25mcg/kg (50umol/kg) for 5 days had 42.03% as
much vascularization in melanoma tumors as control (untreated).
11.1. Male fertility
Ursolic acid, when fed to rats at 5mg/kg bodyweight, was able to
cause infertility by inhibiting spermatogenesis.[63] Specifically,
it causes breaking of bridges in between cells that are soon to be sperm, and
the damaged cells then collect to form symplasts in the Seminiferous Tubules that
are associated with male infertility. It does not appear to cause long-term
damage to the testes.
At least one other in
vitro study noted that ursolic acid was able to reduce sperm
motility.[64]
11.2. DNA
One
study noted that ursolic acid was able to induce cell death in endothelial
cells when the concentration exceeded 12.5uM, and that the mechanism of death
was apoptosis related; DNA strand breaks were noted 6 hours after incubation
via p53.[23] The
DNA strand breaks were later seen in
vivo in ApoE deficient mice when the water was spiked with
10uM or 30uM of ursolic acid.
