By Sasmita Saha

1st Year, M. PharmUnder guidance ofProf. P.D. Mali

SINHGAD COLLEGE OF PHARMACY, VADGAON, PUNE-41

Phytoconstituents effective in Hyperlipidemia

• Hyperlipidemia disease has afflicted humankind since antiquity.

• Hyper(Excess)-Lipid(Fat)-Emia-(A condition of the blood) Hyperlipidemia.

• The treasure house of plant kingdom has a number of plants to treat this ailment. The indigenous system of medicine provides an abundant data about plants available for treatment of hyperlipidemia.

• Adults, age 20+, 15% had HIGH total blood cholesterol levels Mean total blood cholesterol level for adults- 197.7 mg/dL Youth 20.3% had at least one abnormal lipid level(LDL, HDL or Total Serum).

Introduction

Hyperlipidemia/ Hyperlipoproteinemia

• Excess of fatty substances(lipids), largely cholesterol and triglycerides, in blood.

• Also called Hyperlipoproteinemia.

Hyperlipidemia- Elevated blood triglyceride and cholesterol.

Hypertriglyceridemia- Elevated triglyceride

Exaggerated Postprandial Lipemia- Prolonged triglyceride in the blood Fat’s version of hyperglycemia/diabetes. Hypercholesterolemia- Elevated

cholesterol. High LDL-cholesterol and/or Low HDL-

cholesterol Hyperlipoproteinemiaor

Dyslipoproteinemia- Elevated Lipoprotein concentrations Genetic abnormalities or secondary to underlying risks.

Hyperlipidemic Blood

(http://upload.wikimedia.org/wikipedia/en/thumb/8/8d/Hyperlipidaemia__lipid_in_EDTA_tube.jpg/230px-Hyperlipidaemia_-_lipid_in_EDTA_tube.jpg)

Three Types of Lipids- Simple, Compound & Derived Lipids.

• Simple Lipids- Triacylglycerol, Saturated & Unsaturated Fats “Neutral Fats”• Compound Lipids:- Lipid+ another compound.

Simple Lipid + Phosphate = PhospholipidSimple Lipid + CHO Group (Galactose) = Glycolipids.Blood Lipids (Triglyceride, Phospholipid,Or Cholesterol)

+ PROTEIN (Apolipoprotein)= Lipoprotein,5 Types: Chylomicrons, VLDL, IDL, LDL, HDL.

Chylomicrons = Apolipoprotein + Exogenous Triglyceride.

Very-Low Density Lipoproteins (VLDL) = Apolipoprotein + Endogenous Triglyceride (↑ %) + Cholesterol.

• Derived Lipids- like Cholesterol.

Overview- lipid digestionglucose

Na+

glucoseChylomicron

Dietary Lipid

FFA MAG

CholesterolApo-

lipoprotein

Pyruvate

Acetyl CoA

CholesterolHMG-CoA reductase

Malonyl coA

FAGlycerol

MAG

TAG

VLDLIDLLipoprotein

lipaseLDL

Fat, carbohydrate

, protein

ChylomicronRemnants (LDL-R)

Hydrolysis of dietary triacylglycerol's in the lumen of the Intestine.

Uptake of MAG and fatty acids by the enterocytes.

Intracellular transport of long chain fatty acids to the ER.

Synthesis of TAGa. Monoacylglycerol

pathwayb. Glycerol phosphate pathway.

• Packaging of TAG into chylomicrons.• Intracellular transport & secretion of

chylomicrons.

Gut-Triglyceride Production

Xiaoyue Pan ,M. Mahmood Hussain, Gut triglyceride production, Biochimica et Biophysica Acta 1821 (2012) 727–735.

Cellular Mechanism of TAG absorption

Input of cholesterol comes from acetyl

coenzyme A (acetyl-CoA);

And also LDL-C and HDL-C in the blood and the LDL receptors. In

addition, it comes from the chylomicrons

Converted into VLDL ,excreted back into the blood, then IDL and

LDL.With an increase in the

free fatty acids.The remainder gets

converted into bile acid through the enzyme

CYP7A1

Cholesterol Pool

http://www.medscape.org/viewarticle/586792

Cholic acid and chenodeoxycholic acid are the two main, important bile acids

7α-cytochrome P7A1 (CYP7A1), rate limiting step. Synthesis & subsequent excretion only way of

elimination of cholesterol. Solubilize cholesterol in bile, and prevents gall

bladder precipitation. Digestion of dietary triglycerides by acting as

emulsifying agents.

Degradation of Cholesterol

The total bile acid pool is about 2 to 3 grams, liver synthesizes about 0.2 to 0.6 grams daily, and 0.2 to 0.6 gram of bile acid is excreted in the feces.

Role of bile is 2-fold. It is a digestive enzyme, it promotes lipid absorption by surfactant action. Also excreting fluid.

Enterohepatic circulation of bile acid

• Liver X receptor (LXR) activated by increased cholesterol. Cholesterol absorption, increase excretion. Thus induce CYP7A1,

stimulates cholesterol to BA.

Farnesoid X receptor (FXR), activated by bile acids.Negative feedback is the inhibition of CYP7A1.

• .• LDL,("bad" cholesterol) - apolipoprotein B along with cholesterol and other lipids. Test measures the amount of

Lp(a) in the blood to help evaluate a person's risk dyslipidemia.

• ApoB- mostly beta-sheet structure- irreversibly lipid droplets.

• HDL-C ("good cholesterol")- alpha-helices- reversibly lipid droplets.

• During binding to the lipid particles - change their 3D structure.

• IDL-C formed by Apolipoprotein E.

A (apo A-I, apo A-II, apo

A-IV, and apo A-V)

B (apo B48 and

apo B100)

C (apo C-I, apo C-II, apo C-III,

and apo C-IV)

Apo- D, E,H

Apolipoproteins

Desirable: < 14 mg/dL (< 35 nmol/l)Borderline risk: 14 - 30 mg/dL (35 - 75

nmol/l)High risk: 31 - 50 mg/dL (75 - 125

nmol/l)Very high risk: > 50 mg/dL (> 125

nmol/l)

2 Main types of apolipoproteins

Ryan, George M; Julius Torelli (2005). Beyond cholesterol: 7 life-saving heart disease tests that your doctor may not give you. New York: St. Martin's Griffin

Lipoprotein Metabolism

Hormonal regulation on lipolysis

cAMP stimulation & PKA activation:- effects on lipolysis

Pathophysiology of hyperlipidemiaDecreased clearance of triglyceride-rich Lipoproteins-inhibition of lipoprotein lipase and triglyceride lipase, peripheral insulin resistance, carnitine deficiency, and hyperthyroidism Nephrotic syndrome, decreased effective plasma albumin.

ApoE E2/E2 genotype. It is due to cholesterol-rich

VLDL (β-VLDL).

Familial, Acquired (also called secondary), Idiopathic.

UNCLASSIFIED FAMILIAL FORMS- extremely rare:-Hyperalphalipoproteinemia, Polygenic

hypercholesterolemia

CAUSES/ RISK FACTORS1. Life style2. Diabetes(type 2)3. Pregnancy4. Alcohol5. Nephrotic Syndrome6. Environmental and genetic

factors7. Obstructive Jaundice8. Hypothyroidism9. Cushing’s Syndrome10. Anorexia Nervosa

SIGNS AND SYMPTOMS OF HYPERLIPIDEMIA

1. Xanthoma2. Xanthelasma of eyelid3. Chest Pain4. Abdominal Pain5. Enlarged Spleen6. Liver Enlarged7. High cholesterol or triglyceride

levels8. Heart attacks9. Higher rate of obesity and

glucose intolerance10. Pimple like lesions across

body11. Atheromatous plaques in the

arteries12. Arcus senilis13. Xanthomata

Negative consequences of insulin-resistant lipid metabolism.Increased intra-abdominal/organ fat.

Increased lipolysis

Increase in free fatty acids/ increased cytokines/ pro inflammatory factors from fat cells.

Precursor to gluconeogenesis increased hyperglycemia increased VLDL.

Dyslipidemia prevalence in diabetes

Lipid abnormalities in Nephrotic syndrome

Increased hepatic synthesis & decreased clearance circulating

lipoproteins Elevated total & LDL-C.

Severe proteinuria/ hypoalbuminemia

Increased triglycerides with VLDL cholesterol.

Apo B & Apo C11, & Apo CIII elevated.

Serum apo CIII, competitive inhibitor of apo CII, LPL activity is inhibited by increase in

apo CIII/apo CII ratio.

Decreased post-hepatic LPL activity Diminished conversion of VLDL to LDL.

Abnormal HDL, LCAT reduced, reduced HDL3 to HDL2 conversion, so slightly

elevated HDL3, very low HDL2

Decreased LDL receptor, increased HDL urinary loss.

Fig: Mechanisms of hyperlipidemia in nephrotic syndrome. 1.

Overproductionof VLDL. 2. Defective lipolysis. 3.

Decreased LDL receptoractivity.

Mohamed Alaa Eldin Hassan Thabetl*, Jose R. Salcedo2, and James C. M. Chanl, Hyperlipidemia in childhood nephrotic syndrome, PracticalPediatr Nephrol (1993) 7:559-566, IPNA 1993

Lipid abnormalities Hypothyroidism

Lower HMG CoA reductase activity Decreased cholesterol synthesis, & high serum LDL-C & IDL.

Decrease LDL & ABCA1/G5/8- receptor Expression

Decreased clearance of cholesterol

HL,CETP, LPL,LCAT activity is inhibited in low T3 level.

Decreased post-hepatic LPL activity Diminished conversion of VLDL to LDL.

All this ultimately results in

Increased TG, TC, LDL-C, ApoB, VLDL remnants& Chylomicrons

Alcohol induced Lipid abnormalities

• Increased VLDL

Type 4 hyperlipidemia.

• Increased chylomicrons & VLDL level Type V hyperlipidemia.

• LPL deficiency

Decrease conversion of VLDL to LDL subsequently to HDL.

Dyslipidemia in Crushing syndrome

Anorexia Nervosa & Lipid abnormalitiesCholesterol ester transfer protein (CETP) activity is

higher inpatients with anorexia nervosa

CETP activity increases cholesterol turnover as an adaptation to its low intake

Decreased thyroxin activity & increased cholesterol turnover.High lipoprotein & low

adiponectin

Catabolism of cholesterol rich lipoprotein

Higher TC and LDL levels.

Plant Constituents Useful in Hyperlipidemia

1.Polyphenols- includes Flavonoids

Tannins2.Saponin glycosides

3.Coumarins4.Alkaloids (steroidal)

5.Monoterpenes6.Fibers

“Polyphenol" – Largest group of phytoconstituents, compounds exclusively derived from the shikimate/

phenylpropanoid and/or the polyketide pathway, more than one phenolic unit and deprived of nitrogen-based

functions.

Polyphenols- what are that?

Polyhydroxyphenols mainly natural, also synthetic or semisynthetic, organic chemicals have large multiple Phenol [hydroxyl (-OH)] structural units, aromatic benzenoid (phenyl) ring.

Reactive species toward oxidation.

The most abundant polyphenols- Condensed tannins.

Other than these- Flavonoids, Phenolic acids, Antho & Leucoanthocyanidines.

Ellagic acid, core-type

'component' of polyphenols

Quideau, S. P.; Deffieux, D.; Douat-Casassus, C. L.; Pouységu, L. (2011). "Plant Polyphenols: Chemical Properties, Biological Activities, and Synthesis". Angewandte Chemie International Edition 50 (3): 586–621

Classification

Polyphenols

Flavonoids Non Flavonoids Phenolic acids

Flavonol-Myercetin,quercetin, kampferolFlavanols- catechin,

epicatechnsIsoflavones- Geinstein,

Daidzain.Flavones- Apigenin,

luteolinFlavanones- hesperidin,

Naringenin.

Hydrolysabletannins-

Gallo tannin,Ellagi tannin

• Hydroxycinnamic acid,• Hydroxy

benzoic acid

https://www.researchgate.net/publication/6912188

AMPK is a responds to increased cellular AMP-to-ATP ratio and upstream signaling pathways

stimulated by cellular stress.

• Polyphenols [resveratrol (major polyphenol in red wine), apigenin], increases phosphorylation & stimulates AMPK.

• Inactivation of ACC( Acetyl-CoA-Carboxylase).• Prevents lipid accumulation.

Discussion1. AMPk activates- lipid-lowering actions.2. Intracerebral administration, In vivo/vitro exposure to

high glucose dephosphorylates & inactivates AMPk, increases Fatty acid synthesis.

3. Inhibits the activity of AMPKα1, not AMPkα2.4. Decreases phosphorylation of ACC1 & ACC2, resulting

in increased ACC activity. Hepatic lipid accumulation.

1. Acetyl CoA Malonyl CoA.2. 2 isoforms- ACC1 & ACC23. ACC1- lipogenic tissues, Malonyl CoA C2 unit

donor.4. ACC1 & ACC2 in hepG2 cell inactivated by

polyphenols.5. Promote AMPKα1 and -α2 activity, prevents

high glucose induced LIPID ACCUMULATION.

ACC

Polyphenolic compounds- Catechins, 4 main types:

1. (-)-epicatechin (EC)2. (-)-epigallocatechin (EGC)

3. (-)-epicatechin gallate (ECG)4. (-)-epigallocatechin gallate (EGCG)EGCG - most abundant, 58% of the total

catechin

https://www.researchgate.n

et/publication/7270603

Results Treatment with EGCG (200µM) decreased intracellular

total cholesterol up to 28% EGCG and SREBP-1. increases active transcription SREBP-1 (nuclear cell fraction).EGCG treatment decreased inactive precursor form of SREBP-1 (membrane fraction) to undetectable levels. A reduction in cholesterol synthesis, loss of cholesterol and an increase in the conversion of cholesterol into bile acids.

Dose-dependent effects of EGCG on intracellular total

and free cholesterol concentrations. The HepG2 cells were incubated for 24 h with increasing amounts of EGCG, 0-200 µM in 10

mL of medium. Homogenized cells were

extracted with hexane, and total (•) and unesterified

(◊) cholesterol were analyzed using gas

chromatography

Discussion1. Inhibition of cholesterol synthesis,

increase in the efflux of cholesterol from the cell to the medium. Increase conversion of cholesterol to bile acids.

2. At the lowest concentration of EGCG (50µM), decrease in cholesterol synthesis as measured using cell lathosterol.

3. ECGC potent inhibitors of Squalene Epoxidase

BPF- Bergamot Polyphenol Fraction

Neoeriocitrin, neoheperitin, neodesmin,

naringenin, rutin, Meltidiene,

bruteridiene.

Result 1. BPF (10 and 20 mg/kg/daily; n=10 for each dose) 30 days,

reduction in tChol, cLDL &TG, an effect accompanied by moderate elevation of cHDL.

2. Increased fecal output of total bile acids and neutral sterols.

3. BPF as post-statin treatment- reduction in tChol & cLDL without re-appearance of side effects.

4. 24 hr. urinary MVA excretion decreased from baseline value.Discussion

1. Naringin and Neohesperidin- reduced activity phosphatidate phosphohydrolase; reduces hepatic TG accumulation.

2. Decrease- apoB-lipoproteins avilability, by reduced acyl CoA: cholesterol acyltransferases (ACAT) activity.

3. Selective inhibition of HMG-CoA reductase.

Flavonoids?

Mechanism of action of Flavonoids in

Hyperlipidemia Lipid peroxidation- common consequence of oxidative stress.

Flavonoid protect lipids against oxidative damage.1. ROS suppression.2. scavenging ROS3. upregulation or protection of antioxidant defenses

Chelate metal ions (iron, copper, etc.), flavonoids inhibits radical generation.

Flavonoid(OH) + R• > flavonoid(O•) + RH Quercetin- iron-

chelating and iron-stabilizing properties.

3′,4′-catechol structure in the B ring- enhances inhibition of lipid peroxidation

(a) Scavenging of ROS (R) by flavonoids (Fl-OH) and (b) binding sites for trace metals

where Me+ indicates metal ions.http://dx.doi.org/10.1155/2013/162750

• Anthocyanidin, luteolin, apigenin, catechin and rosmarinic acid• Arteriosclerosis index:-

• Result:- Decreased serum lipid levels and adipose tissue lipid accumulation, inhibit lipid peroxidation

Effect of tangerine-peel extract and bioflavonoid (hesperidin,naringin) on

HMG-CoA reductase and (ACAT)

Effect on excretion of fecal neutral sterols

Mechanism of action of saponins in Hyperlipidemia

• Precipitating cholesterol from micelles & inhibits bile acid circulation

• Increase LDL receptor activity & LDL-C excretion.• Inhibits pancreatic lipase. VLDL.

2

Isolated compounds: - imperatorin, iso-imperatorin, iso scopoletin, scoparon, anhydroaegeline, xanthotoxol, xanthotoxin , UMBELLIF-ERONE, ESCULETIN, AEGELINE, marmeline, halfordinol, ethyl ether

aegeline, methyl ether aegeline.

Herb Containing Coumarins *

Result and Discussion

1. Aegeline- Reduced plasma triglyceride, TC and FFA accompanied with increase in HDL dyslipidemic hamster model, (50 mg/kg B.W).

2. Aegeline- (phenyl ethanolamine ring) β-3 receptor agonist, cAMP thus lipolysis.

3. This study for the first time demonstrates that Coumarines may be account for antiobesity activity of leaf extracts and may act depleting fat storage by lipolysis.

4. Esculetin- induction of apopotosis, inhibition of adipogenesis.Umbellifer

on

EsculetinAegeline

Monoterpenes on lipid lowering 1

• Suppression of HMG-CoA reductase.• Upregulation of liver LDL receptor.• LDL receptor in liver, stimulation of cholesterol

clearance.

Glycerol-3-phosphate Phosphatidic acid Di-acyl-glycerol

PAP

Malondialdehyde Biomarker of lipid peroxidation Active constituents- Allin, Allyl propyl disulfide,

Diallyl disulfide(allicin), diallyl trisulfide & Non sulfur- N-fructosyl-arginine, N-fructosyl glutamate.

Effect of EugenolAntioxidant function,

Eugenol & BHA- inhibition of iron-dependent lipid peroxidation, &

copper dependent LDL.

Alkaloids (Steroidal moiety)

Conclusion:-

Commiphora mukul (guggul lipid)- Medicinal plant in hyperlipidemia treatment over 2500 years.

Plantsterols (β- sitosterols)- blocks CH uptake in intestine. Most research is ongoing under- ICMR. Most work had been done on flavanol compounds

belonging to polyphenolic group. Green tea ( 100-600mg/ml) polyphenol have rich in

FAVANOL content, but than that favanol content is higher in DARK CHOCOLATE. (460-610mg/ml).

Researches are ongoing to effectively utilize the flavanols ( Flavan-3-ols) in dark chocolates [ Cocoa beans- (-) epicatechin & (+) catechin].

References:-1. Vincenzo Mollace, Iolanda Sacco b, Elzbieta Janda, et al.

Hypolipemic and hypoglycaemic activity of bergamot polyphenols: From animal models to human studies; Fitoterapia,2011,82; 309–316.

2. T. Gohil1, N. Pathak1, N. Jivani, et al. Treatment with extracts of Eugenia jambolana seed and Aegle marmelos leaf extracts prevents hyperglycemia and hyperlipidemia in alloxan induced diabetic rats; African Journal of Pharmacy and Pharmacology,2010,4(5);270-275.

3. Mengwei Zang, Shanqin Xu,Karlene A. Maitland-Toolan, et al. Polyphenols Stimulate AMP-Activated Protein Kinase, Lower Lipids, and Inhibit Accelerated Atherosclerosis in Diabetic LDL Receptor–Deficient Mice; article in diabetes; 2006,55, 2180-2191.

4. San-Hu Gou, Hai-Feng Huang,Xin-Yue Chen, et al. Lipid-lowering, hepatoprotective, and atheroprotective effects of the mixture Hong-Qu and gypenosides in hyperlipidemia with NAFLD rats; Journal of the Chinese Medical Association, 2016,79,111-121.

5. Thirunavukkarasu Thirumalai1, Narayanaswamy Tamilselvan1, Ernest David; Hypolipidemic activity of Piper betel in high fat diet induced hyperlipidemic rat; Journal of Acute Disease; 2014,131-135.

References:-6. Daljit Singh Aroral, Jemimah Gesare Onsare1 and Harpreet Kaur, Bioprospecting of Moringa (Moringaceae): Microbiological Perspective; Journal of Pharmacognosy and Phytochemistry;2013, 1(6); 193-215.7. James S Lin, An alternative treatment of hyperlipidemia with red yeast rice: a case report, Journal of Medical Case Reports 2010, 4:4; 1-3.8. Li-Jun Feng, Chen-Huan Yu, Ke-Jing Ying, et al. Hypolipidemic and antioxidant effects of total flavonoids of Perilla Frutescens leaves in hyperlipidemia rats induced by high-fat diet; Food Research International,2011, 44; 404–409.9. Nishant P. Visavadiya and A. V. R. L. Narasimhacharya; Asparagus Root Regulates Cholesterol Metabolism and Improves Antioxidant Status in Hypercholesteremic Rats; eCAM 2009, 6(2); 219–226.10. Christina a. Bursill,and paul d. Roach, Modulation of Cholesterol Metabolism by the Green Tea Polyphenol (-)-Epigallocatechin Gallate in Cultured Human Liver (HepG2) Cells, Journal of agricultural and food chemistry ,2006, 1-7.11. Nishant P. Visavadiya1,and A. V. R. L. Narasimhacharya, Ameliorative Effects of Herbal Combinations in Hyperlipidemia; Oxidative Medicine and Cellular LongevityVolume 2011,160408,1-9.12. Esfandiar Heidarian, Effat Jafari-Dehkordi,Ali Seidkhani-Nahal, Effect of garlic on liver phosphatidate phosphohydrolase and plasma lipid levels in hyperlipidemic rats; Food and Chemical Toxicology,2011,49, 1110–1114.

References:-13. Xiaoyue Pan ⁎, M. Mahmood Hussain, Gut triglyceride production, Biochimica et Biophysica Acta,2012, 1821; 727–735.14. Manal f. Ismail, Mohamed z. Gadu and Mohamed A. Hamdy; Study of the hypolipidemic properties of pectin, garlicn And ginseng in hypercholesterolemic rabbits, Pharmacological Research, 1999, 39(2);157-164.15. Xiaojun KONG, Xiwang LIU, Jianyong LI, Yajun Yang; Advances in Pharmacological Research of Eugenol; Curr Opin Complement Alternat Med; 2014, 1:1, 8-11.16. Aniket Karmase, Rahul Birari, Kamlesh K. Bhutani; Evaluation of anti-obesity effect of Aegle marmelos leaves; Phytomedicine, 2013,20; 805– 812.17. Samer Megallia, Fugen Aktanb, Neal M. Daviesc, Basil D. Roufogalisa; Phytopreventative Anti-Hyperlipidemic Effects Of Gynostemma Pentaphyllum In Rats; J Pharm Pharmaceut Sci, 2005, 8(3); 507-515.18. K.Harikumar,S. Abdul Althaf, B. Kishore kumar, M. Ramunaik, CH. Suvarna; A Review on Hyperlipidemic; International journal of novel trends in pharmaceutical sciences, 2013, 3(4), 50-71.19. Song-Hae Bok,Sung-Heui Lee,Yong-Bok Park; Plasma and Hepatic Cholesterol and Hepatic Activities of 3-Hydroxy-3-methyl-glutaryl-CoA Reductase and Acyl CoA: Cholesterol Transferase Are Lower in Rats Fed Citrus Peel Extract or a Mixture of Citrus Bioflavonoids; J. Nutr., 1999,129; 1182–1185.

References:-20. Ashok Kumar Gupta, Mansi Verma, Gajraj Singh Lodhi; Protective effect of Ficus infectoria plant extract against fructose induced hyperlipidemia and hyperglycemia in rats, The Journal of Phytopharmacology, 2014, 3(6); 431-435. 21. Vijai Lakshmia, Shishir Srivastav, Ashok Kumar Khanna, Abbas Ali Mahdi, Santosh Kumar Agarwal; Lipid Lowering potential of Andrographis paniculata (Nees), The Journal of Phytopharmacology, 2014, 3(2); 124-129.22. Hesham Abdul Aziz, Yvonne Tze Fung Tan, Kok Khiang Peh, Mun Fei Yam; Direct effect of khat and garlic extracts on blood lipids contents: Preliminary in vitro study, Obesity Research & Clinical Practice; 2010, 4; e247—e252.24. Yueshan Hua,, Erik A. Ehli, Julie Kittelsrudc, Patrick J. Ronanb et al. ; Lipid-lowering effect of berberine in human subjects and rats; Phytomedicine; 2012,19; 861– 867.25. Fernanda Martins1, Tatiana M. Noso1, Viviane B. Porto1 et al. Maté Tea Inhibits In Vitro Pancreatic Lipase Activity and Has Hypolipidemic Effect on High-fat Diet-induced Obese Mice, Obesity,2009, 18; 42–47.26. Yi Jia,Zhuo-Ying Li,Hai-Gang Zhang; Panax notoginseng saponins decrease cholesterol ester via up-regulating ATP-binding cassette transporter A1 in foam cells, Journal of Ethnopharmacology, 2010, 132; 297–302.27. AA Adeneyea, JA Olagunjub, Preliminary hypoglycemic and hypolipidemic activities of the aqueous seed extract of Carica papaya Linn. in Wistar rats; Biology and Medicine, 2009, 1 (1); 1-10.