Fat

Fatty Acid Metabolism in Humans

Fat and Lean Interactions

Lean

Body

MassAdipose

tissue


• Virtually all fatty acids originate from dietary

triglyceride fatty acids.

• Long-term storage site is adipose tissue.

• Regulated release of fatty acids as free fatty acids

provides the majority of lipid fuel for postabsorptive

adults.


Oxidation

100 gm

TG fatty acids

Chylomicron TG

100 gmFFA

Direct Oxidation

CO2 + H2O(20-70 gm)

Adipose tissue

(30-80 gm)

FFA: free fatty acids

TG: triglycerides

Adipose PhysiologyInsulin

Adipocyte

Triglycerides

FFA

Glycerol


Adipose PhysiologyGrowth hormone

catecholamines

Adipocyte

Triglycerides

FFA

Glycerol


Adipose Physiology

Adipocyte

Triglycerides

FFA

Glycerol

Growth hormone

catecholamines


Relationship Between Body Composition and Physiological Consequences

• Body fat distribution and free fatty acids (FFA)• Adipose tissue FFA release• Effects of excess FFA on health

Body Fat Distribution and Free Fatty Acids (FFA)

Normal FFA High FFA

Intra-abdominal (Visceral) Fat and Upper Body Obesity

Subcutaneous fat

Intra-abdominal fat

FFA

Upper Body / Intra-abdominal (Visceral) Obesity and Insulin Resistance

Insulin

resistance

Glucose

release

Constriction

Relaxation

Insulin

secretion

Muscle Vasculature

Liver Pancreas

Upper body /

Intra-abdominal obesity

Insulinresistance

Free Fatty Acids (FFA) and PancreasInsulin resistance FFA

• Long-term damage to

beta cells

• Decreased insulin

secretion

Short-term stimulation

of insulin secretion

Pancreas

Adipose tissue

Free Fatty Acids (FFA) and Dyslipidemia

Liver

VLDL-TG

HDL cholesterol

Apo B100 synthesis

and secretion

Insulin resistance FFA

Adipose tissue

TG: triglycerides

Free Fatty Acids (FFA) and Glucose Production


Adipose tissue

Liver

Glucose release

Skeletal

muscle

cells

Free Fatty Acids (FFA) and Muscle

Intra-

muscular

TG

Insulin resistance

Glucose uptake

Muscle


Adipose tissue

TG: triglycerides

Free Fatty Acids (FFA) and Hypertension

Relaxation – decreased nitric oxide generation

Vasculature

Constriction –

greater response

to alpha-

adrenergic stimuli


Adipose tissue

Body Fat Distribution and Free Fatty Acids (FFA)

• Upper body obesity is associated with adverse metabolic consequences.

• Upper body obesity is associated with high basal and postprandial

FFA.

• Intra-abdominal (visceral) fat most strongly correlated with

metabolic abnormalities.

• Do the excess FFAs come from intra-abdominal fat?

Regional Adipose Tissue Model

Intra-abdominal

(visceral) fat

Lower body

subcutaneous fat

Upper body

subcutaneous fat

Summary

• Upper body subcutaneous fat accounted for the

majority of systemic free fatty acid (FFA) release.

• Intra-abdominal (visceral) fat mass correlated with

but was not the source of most systemic FFA release.

• Intra-abdominal fat mass predicts greater delivery of

FFA to the liver from intra-abdominal lipolysis.

• A greater portion of free fatty acid (FFA) appearance

derives from leg and splanchnic adipose tissue in

obese than lean men and women.

Cont….

• Nevertheless, the majority of systemic FFAs originate from upper

body subcutaneous fat in obese men and women.

• Intra-abdominal (visceral) fat correlates positively with the

proportion of hepatic FFA delivery from intra-abdominal fat in

both men and women.

• Upper body obesity is associated with high free fatty acids (FFA) due to excess release from upper body subcutaneous fat.

• High FFA can result in:

• insulin resistance in muscle and liver

• VLDL TG

• insulin secretion (?diabetes)

• Vascular abnormalities

Conclusions

• In both men and women, greater amounts of intra-

abdominal (visceral) fat result in a greater

proportion of hepatic free fatty acid (FFA) delivery

originating from intra-abdominal adipose tissue

lipolysis in the overnight postabsorptive state.

• This implies that arterial FFA concentrations will

underestimate hepatic FFA delivery systematically

and progressively with greater degrees of intra-

abdominal adiposity.

Cont…

• Fat is a dynamic and varied tissue.

• Regional differences in adipose biology affect health.

• The causes of differences in body fat distribution are unknown.

• The relative contributions of high free fatty acids and adipokines to adverse health is unknown.

Hyperlipidemia

• Hyperlipidemia Hyperlipoproteinemia means abnormally increased plasma lipoproteins-one of the risk factors for atherosclerosis (deposition of fats at walls of arteries, forming plaque)

• Other risk factors-Cigarette smoking, Diabetes, another source of oxidative stress. Also, obesity and, hypertension.

• Hyperlipemia denotes increased

levels of triglycerides.

• Such abnormality is extremely

common in general population,

regarded as highly modifiable

risk factor for cardio vascular

diseases, due to influence of

cholesterol.

INTRODUCTION

Plasma lipids include: cholesterols, triglycerides and phospholipids.Lipids are insoluble in plasma and are transported in protein capsule known as LIPOPROTEIN

Types of lipoproteins1. Chylomicrons (TGs): → formed in GIT from dietary

TG.

2. VLDL (TGs and cholesterol) → endogenously synthesized in liver. Degraded by LPL into free fatty acids (FFA) for storage in adipose tissue and for oxidation in tissues such as cardiac and skeletal muscle.

3. IDL (TGs, cholesterol); and LDL (cholesterol) → derived from VLDL hydrolysis by lipoprotein lipase.Normally, about 70% of LDL is removed from plasma by hepatocytes.

4. HDL (protective) →exert several anti atherogeniceffects. They participate in retrieval of cholesterol from the artery wall and inhibit the oxidation of atherogenic lipoproteins& removes cholesterol from tissues to be degraded in liver.

Composition Density Size

Chylomicrons TG >> C, CE Low Large

VLDL TG > CE

IDL CE > TG

LDL CE >> TG

HDL CE > TG High Small

Causes of Hyperlipidemia

• Diet

• Hypothyroidism

• Nephrotic syndrome

• Anorexia nervosa

• Obstructive liver disease

• Obesity

• Diabetes mellitus

• Pregnancy

• Obstructive liver disease

• Acute heaptitis

• AIDS (protease inhibitors)

Dietary sources of Cholesterol

Type of Fat Main Source Effect on

Cholesterol levels

Monounsaturated Olives, olive oil, canola oil, peanut oil,

cashews, almonds, peanuts and most

other nuts; avocados

Lowers LDL, Raises

HDL

Polyunsaturated Corn, soybean, safflower and cottonseed

oil; fish

Lowers LDL, Raises

HDL

Saturated Whole milk, butter, cheese, and ice cream;

red meat; chocolate; coconuts, coconut

milk, coconut oil , egg yolks, chicken skin

Raises both LDL and

HDL

Trans Most margarines; vegetable shortening;

partially hydrogenated vegetable oil; deep-

fried chips; many fast foods; most

commercial baked goods

Raises LDL

Hereditary Causes of Hyperlipidemia

• Familial Hypercholesterolemia

• Codominant genetic disorder, Occurs in heterozygous form

• Occurs in 1 in 500 individuals

• Mutation in LDL receptor, resulting in elevated levels of LDL at birth and

throughout life

• High risk for atherosclerosis, tendon xanthomas (75% of patients), tuberous

xanthomas and xanthelasmas of eyes.

• Familial Combined Hyperlipidemia

• Autosomal dominant

• Increased secretions of VLDLs

• Dysbetalipoproteinemia

• Affects 1 in 10,000

• Results in apo E2, a binding-defective form of apoE (which usually plays

important role in catabolism of chylomicron and VLDL)

• Increased risk for atherosclerosis, peripheral vascular disease

• Tuberous xanthomas, striae palmaris

Types of HyperlipidemiaFRERICKSON CLASSIFICATION- based on the pattern of

lipoprotein on electrophoresis or ultracentrifugation.

• Primary Chylomicronemia (I): Chylomicrons are not present in the serum of normal individuals who have fasted 10 hours. The recessive traits of deficiency of lipoprotein lipase or its cofactor are usually associated with severe lipemia.

• Familial Hypercholesterolemia (IIA): Familial hypercholesterolemia is an autosomal dominant trait. Although levels of LDL tend to increasewith normal VLDL.

• Familial Combined (mixed) Hyperlipoproteinemia (IIB):elevated levels of VLDL, LDL.

• Familial Dysbetalipoproteinemia (III): Increased IDL resulting increased TG and cholesterol levels.

• Familial Hypertriglyceridemia (VI): Increase VLDL production with normal or decreased LDL.

• Familial mixed hypertriglyceridemia (V): Serum VLDL and chylomicrons are increased

Diagnosis of hyperlipidemia

• Diagnosis is typically based on medical history, physical examination and blood test done after overnight fasting.

Management of Hyperlipidemias

I- Diet:

• Avoid saturated fatty acids (animal fats) and give unsaturated fatty acids (plant fats).

• - Regular consumption of fish oil which contains omega 3 fatty acids and vitamins E and C (antioxidants).

II. Exercise:

• - ↑ HDL and insulin sensitivity.

III- Drug therapy: the primary goal of therapy is to decrease levels of LDL . Also,increase in HDL is recommended.

Medications for Hyperlipidemia

Drug Class Agents Effects (% change) Side Effects

HMG CoA reductase

inhibitors

Lovastatin

Pravastatin

LDL (18-55), HDL (5-15)

Triglycerides (7-30)

Myopathy, increased liver

enzymes

Cholesterol

absorption inhibitor

Ezetimibe LDL( 14-18), HDL (1-3)

Triglyceride (2)

Headache, GI distress

Nicotinic Acid LDL (15-30), HDL (15-35)

Triglyceride (20-50)

Flushing, Hyperglycemia,

Hyperuricemia, GI distress,

hepatotoxicity

Fibric Acids Gemfibrozil

Fenofibrate

LDL (5-20), HDL (10-20)

Triglyceride (20-50)

Dyspepsia, gallstones,

myopathy

Bile Acid

sequestrants

Cholestyramine LDL

HDL

No change in triglycerides

GI distress, constipation,

decreased absorption of

other drugs

REFERENCE:

K.D.Tripathi, Essentials of Medical Pharmacology, 6th Edition, PgNo. 612-626.

Goodman & Gilman’s, The Pharmacological Basis Of Therapeutics, 11th

Edition, PgNo. 933-965.

INTERNET.

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