Regulation metabolism in liver

Regulation of nutrients metabolism in liver

(BIOC 315) Part 1

1

Dr. Othman Baothman

General description of the liver

؟ةجسنلأا نم هريغ نع دبكلا زيمي يذلا ام

• The adult human liver weighs 1–1.5 kg.

• It is the largest internal organ, and the body’s second largest, after the skin.

• Liver metabolism is very complex. It is the organ which is first exposed to blood coming from the gut through the hepatic portal vein.

• Liver is able to perform all the interconversion between lipid, carbohydrate and amino acids.

يلاوح غلابلا ناسنلإا يف دبكلا نزي - 1

- 1.5 وضع مخضأو ،يلخاد وضع ربكأ وهف ،مجك

دلجلا دعب . ءاعملأا نم مداقلا مدلل ضرعتي وضع لوا وهف ،ةدقعم دبكلا يف ةيضيلأا تايلمعلا - نع وملا ةيئاذغلا تانوكملل ةباجتسلإا وه هفئاظو دحأو ،يدبكلا يبابلا ديرولا قيرط يف ةدوج

حاتم وه امب ةءافك رثكلأا مادختسلاا يحلا نئاكلل نكمملا نم هلعجت ثيحب ،ءاذغلا .

- يملأا ضامحلأاو تارديهوبركلاو نوهدلا نيب تلاوحتلا لك يدؤيل ًايلمعرداق دبكلا

ةين .تاييدثلا ةيلخ يف ةنكمملا

2

• Liver is only the organ able to produce ketone bodies from fatty acids

• Liver is only the site of urea biosynthesis

• Liver is the major site for fatty-acid and steroid biosynthesis.

• Liver the only site for the processing of dietary lipid into lipoproteins.

• The liver stores glucose as glycogen and synthesizes glucose by gluconeogenesis during starvation.

- ةينهدلا ضامحلأا نم تانوتيكلا جاتنا ىلع رداقلا ديحولاوضعلا وه دبكلا .

- ايرويلل يويحلا عينصتلل ديحولا ناكملا طقف وه دبكلا .

- ديوريتسلاو ةينهدلا ضامحلأا عينصتل يسيئرلا ناكملا وه دبكلا .

- ةينهدلا تانيتوربلا ىلإ ةيئاذغلا نوهدلا ةجلاعمل ديحولا ناكملا دبكلا .

- ةيلمع قيرط نع زوكولجلا عنصيو نيجوكيلج ةروص يف زوكولجلا نزخي دبكلا ثادحتسا

ركسلا gluconeogenesis ( )

ةعاجملا ءانثأ .

General description of the liver

؟ةجسنلأا نم هريغ نع دبكلا زيمي يذلا ام

3

مقر لكش 1

Two major vessels (See Figure 1):

• Hepatic artery(supplies about 20% of the blood): carry the oxygenated blood coming from the heart.

• Portal vein: Carry the substances absorbed from the intestinal tract (monosaccharides and amino acids) and then transported first to the liver then to the general circulation.

– امه نييسيئر نييئاعو نم نوكتي (

ةروصلا رظنا

مقر :)1

– يدبكلا نايرشلا (

يلاوحب دبكلا دميو 20

مدلا نم ٪

:) .بلقلا نم مداقلا دسكؤملا مدلا لمحي – يدبكلا يبابلا ديرولا :

نم ةصتمملا داوملا لمحي

ءاعملأا ( ينيملأا ضامحلأاو ةيداحلأا تايركسلا لثم ة

) .ةيومدلا ةرودلا ىلإ مث ،دبكلا ىلإ لاوأ اهلقن مث نمو

The major vessels of the liver

دبكلا يف ةيسيئرلا ةيعولأا

1. Regulation metabolism in the liver during fed state

5

A. Carbohydrate metabolism B. Fat metabolism

C. Protein metabolism

2. Regulation metabolism in the liver during fasting

A. Carbohydrate metabolism B. Fat metabolism

C. Protein metabolism

1. Regulation metabolism in the liver during fed state

6

A. Carbohydrate metabolism during fed state

عبشلا ةلاح يف دبكلا يف تارديهوبركلا ضيا



Glucose is absorbed from the intestine into the portal vein where its concentration may reach almost 10 mM after meal.



This increased use of glucose is not a result of stimulated glucose transport into the hepatocyte, because this process is normally rapid and GLUT-2 is not influenced by insulin.

 يف ديرولا لخاد ىلا ءاعملأا نم زوكولجلا صاصتما متي ،عبشلا ةلاح يبابلا

نيتورب لقان قيرط ،صصختم ي

ىمسي GLUT-2 ةيلخلا لخاد ىلإ وا نم يولخلا ءاشغلا ربع زوكولجلا لقنب موقي .

دحأ وه لقانلا اذهو 14

لقانلا اذه هيف دوجوملا جيسنلا عون بسح فلتخت ةعونتملا لقاونلا نم اعون (

لودج رظنا 1

.)

Rather, hepatic metabolism of glucose is increased by the following mechanisms:

7

زوكولجلا لقاون

• Table 1. Glucose transporters

Mechanisms of increased glucose in fed state

1. Increased phosphorylation of glucose:

High level of glucose in the heptocytes allow glucokinase (GK) (or hexokinase 4) to phosphorylate glucose to G6P (see fig 2 (1)).

This contrasts with the post-absorptive state in which hepatic glucose levels are lower and glucokinase is largely inactive because of its low affinity (high K

_m

) for glucose.

زوكولجلا ةرفسف ةدايز :

دبكلا ايلاخ يف زوكولجلا ىوتسم عافترا زانيكوكولغ ميزنلأ حمسي

(GK)

( زانيكوسكيه وأ 4

) ىلإ زوكولجلا رفسفي نأ ام ةلاح سكعب اذهو ، G6P

فخنت دبكلا يف زوكولجلا تايوتسم نأ ثيح تاعاسب لكلأا دعب لقيو ض

خنم هليضفت ببسب زانيكوكولغ ميزنأ ةيطاشن ريبك لكشب زوكولجلل ضف

.

10

Major metabolic pathways in liver in the absorptive state

Figure 2

¹¹

In fed state

2. Increased glycogen synthesis:

G6P

glycogen synthase

glycogen

12

3. Increased activity of the hexose monophosphate pathway (HMP)

(see Figure 2, ③).

4. Increased glycolysis

(See Fig 2, 4)

5. Decreased gluconeogenesis - Pyruvate carboxylase inactive

- The high level of insulin in the absorptive period also favors inactivation of other enzymes unique to gluconeogenesis, such as fructose 1,6-bisphosphatase

فسوفلا يداحأ زوسكيه ركسل يضيلأا راسملا طاشن ةدايز تا

للحتل يضيلأا راسملا ةدايز زوكولجلا

ركسلا عينصتل يضيلأا راسملا ضافخنا

In fed state

B. Fat metabolism in the liver during fed state

• Increased fatty acid synthesis

- Liver is the primary tissue for de novo synthesis of fatty acids

(see Figure 2, ⑤).

- Fatty acid synthesis is favored by the availability of substrates (acetyl CoA and NADPH derived from the metabolism of glucose).

•

Increased TAG synthesis

TAG synthesis is favored because fatty acyl CoA is available both from de novo synthesis from acetyl CoA and from hydrolysis of the TAG component of

chylomicron remnants removed from the blood by

hepatocytes. (see Figure 2,

6

).

17

Major metabolic pathways in liver in the absorptive state

Figure 2

¹⁸

C. Protein metabolism in the liver during fed state

• Increased amino acid degradation:

In the absorptive period:

- Protein synthesis

- Deaminatedand converted to

- TCA cycle intermediates for energy or used in fatty acid synthesis (see Figure 2, 7 ).

• Increased protein synthesis:

Because protein cannot be stored like glycogen or TAG, the increase in the synthesis of hepatic proteins result in

replacement of any proteins that have been degraded during the previous postabsorptive period (see Figure 2, 8

)

.

21

2. Regulation metabolism in liver

during fasting

Fuels stores in the body during fasting

لكشلا لباقملا ( لكش مقر 6 ) حضوي ىدم رفوت دوقولا

يضيلأا يف

مظعم ةجسنا مسجلا صخشلل علا

يدا

وذ نزو 70 مجك ًابيرقت يف ةيادب مايصلا . و ظحلان

نأ نزخلا لئاهلا نم تارعسلا ةيرارحلا

فوتملا ةر

يه نوهدلا نوكتو ةنزخم يف ةروص يارت

ديارسيلج (Triglyceride, TAG)

- يهو ةيفاك

تاجايتحلإ ةقاطلا

ةدمل 3 رهشا - ةنراقم عم

نيجوكيلجلا .

ظحلانو هنأ

ىلع مغرلا نم نأ

نيتوربلا ربتعي

ردصم

،ةقاطلل نإف لك رب نيتو

هيدل

،ةفيظو لثم تاميزنلاا اهريغو

. اذهلو نإف

يلاوح ثلث نيتوربلا يف

مسجلا نكمي تسا همادخ

جاتنلإ ةقاطلا .

23

مقر لكش 6

2. Carbohydrate metabolism in liver during fasting

The liver first uses glycogen degradation and then gluconeogenesis to maintain blood glucose levels to sustain energy metabolism of the brain and other glucose-requiring tissues.

نمو نيجوكيلجلا مده دبكلا مدختسي ةيادب ،مايصلا ةلاح يف عينصت مث

لع ظافحلل مدلا يف ركسلا تايوتسم ىلع ظافحلل ركسلا ضيأ ى

زوكولجلل ةجاتحملا ةجسنلأا نم اهريغو غامدلا يف ةقاطلا .

كلل يئاذغلا ليثمتلل ناثدحت نيتلاح مها ىلع زكرنس اذهلو تارديهوبر

( زوكولجلا )

يهو مايصلا ةلاح يف دبكلل :

A. Increased glycogen degradation B. Increased gluconeogenesis

24

Figure 7. Sources of blood glucose after ingestion of 100 g of glucose.

25

During fasting:

A. Increased glycogen degradation

Figure 7 shows the sources of blood glucose after ingestion of 100 g of glucose. During the brief absorptive period, glucose from the diet is the major source of blood glucose. Several hours after the meal, blood glucose levels have declined sufficiently to cause increased secretion of glucagonand decreased release of insulin. The increased glucagon to insulin ratio causes a rapid degredation of liver glycogen stores (which contain about 80 g of glycogen in the well-fed state).

Note that liver glycogen is nearly exhausted after 10–18 hours of fasting; therefore, hepatic glycogenolysis is a transient response to early fasting.

• The Pathways of Glycolysis and Gluconeogenesis and their

Hormonal Regulation

•

ينصتو للحت تاراسم ع

اهميظنتو ركسلا ينومرهلا

• The Pathways of Glycolysis and Gluconeogenesis and their

Hormonal Regulation

•

ينصتو للحت تاراسم ع

اهميظنتو ركسلا ينومرهلا

مقر لكش

29

9

Three places in which the pathways of glycolysis and gluconeogenesis are

separate

• GK/G6pase.

• PFK/FBP.

• PK/PC and PEPCK.

30

لكشلا تارصتخم 9

Substrates: G 6-P, glucose 6-phosphate; F 6-P, fructose 6-phosphate; F 1,6-P2, fructose 1,6 bisphosphate; F 2,6-P2, fructose 2,6-

bisphosphate; Glyc 3-P, glyceraldehyde 3-phosphate; DHAP, dihydroxyacetone phosphate; PEP, phosphoenolpyruvate.

Enzymes: GK, glucokinase; G-6-Pase, glucose-6-phosphatase; PFK, phosphofructokinase; FBP, fructose-1,6 bisphosphatase; PK, pyruvate kinase; PC, pyruvate carboxylase; PEPCK, phosphoenolpyruvate carboxykinase; Glyc-K, glycerol kinase; LDH, lactate dehydrogenase;

AAT, alanine aminotransferase.

The enzyme marked BFEis a single, bifunctional enzyme known as 6- phosphofructo-2-kinase/fructose-2,6-bisphosphatase, responsible for formation and breakdown of F 2,6-P₂, a compound with a important role in regulation of these pathways.

31

B. Increased gluconeogenesis

• The carbon skeletons for gluconeogenesis are derived primarily from gluconeogenic amino acids and lactate from muscle, and glycerol from adipose (See slide

• Gluconeogenesis plays an essential role in

maintaining blood glucose during both

overnight and prolonged fasting. (see Figure

8).

During fasting

Glycogen degradation as part of the overall metabolic response of the liver.

34

Figure 8

1. Regulation of glucokinase (GK) in glucogenogensis

ميزنا ميظنت متي فيك زانيكوكولجلا

؟ زوكولجلا عينصت راسم ثادحتسا دنع

مقر لكش

35

10

• Gluconeogenesis, favored by activation of fructose 1,6-bisphosphatase (FBP) (due to a drop in its inhibitor, fructose 2,6-bisphosphate and by induction of phosphoenolpyruvate carboxykinase (PEPCK) by glucagon, begins four to six hours after the last meal and becomes fully active as stores of liver glycogen are depleted.

36

ةفيظولا جودزملا ميزنأ رود

Bifunctional enzyme (BFE)

يف

gluconeogenesis مقر لكش

11

(PKA)

The precursors for gluconeogenesis?

ةيلولأا تانوكملا (

فئلاسلا )

؟ركسلا ثادحتسلا

• The most important precursors for gluconeogenesis are: lactate, glycerol and the amino acids

• Lactate: is produced from glucose degradation in such tissues e.g.

muscle, red cells and kidney, a cycle exist between lactate

production in theses tissues and its conversion to glucose. This cycle is called Cori cycle (see figure 12). Therefore , from lactate there is no net glucose production for oxidation by such tissues e.g brain.

• ةيلولأا تانوكملا (

فئلاسلا ) يه ركسلا ثادحتسلا ةيمهأ رثكلأا :

سلجلا ،تاتكلالا

نير ةينيملأا ضامحلأاو

• تاتكلالا : لاخو تلاضعلا لثم ةجسنلأا ضعب يف زوكولجلا للحت نم هجاتنإ متي مدلا اي

ةيلكلاو ءارمحلا

، يف تاتكلالا جاتنإ نيب ةرود نوكتت ثيح ىلإ اهلوحتو ةجسنلأا هذه

زوكولج . يروك ةرود ةرودلا هذه ىمستو (

لكشلا رظنا 12

.) كانه نوكي نل ،يلاتلابو

خملا قيرط نع هتدسكل تاتكلالا نم زوكولجلل يفاص جاتنإ .

40

Cori cycle

41

مقر لكش

12

• Glycerol: during starvation, TAG stores in the adipose tissue are mobilized by hydrolysis to fatty acids and glycerol: the fatty acids are transported to other tissues to provide a fuel of respiration.

• The glycerol is transported to liver by glycerol kinase, then can be

phosphorylated. The resulting glycerol phosphate can be used to form TAG in the liver, or can be converted to dihydroxyacetone phosphate (DHAP) by reversal of the glycerol phosphate dehydrogenase reaction (see Figure 13).

DHAP can participate in glycolysis or gluconeogenesis.

• نيرسلجلا ( وا لورسلجلا :) نإف ،ةعاجملا للاخ لحتلا قيرط نع لقنت ةينهدلا ةجسنلأا يف ةنزخملاTAG

ل.سفنتلل دوقولا ريفوتل ىرخلأا ةجسنلأا ىلإ لقتنت ةينهدلا ضامحلأا .لورسلجو ةينهد ضامحأ ىلا يئاملا

• امأ لورسلجلا ميزنا قيرط نع دبكلا ىلإ لقتني هنإف زانيك

نيرسلجلا (glycerol kinase) ثيح ،

رفسفتي

لورسلجلا تافسوفلا نيرسلج ىلا (

(glycerol phosphate نيوكت يف مدختسي يذلا

وأ ،دبكلاTAG

نوتيسأ يسكورديه يئانث تافسوفلا ىلإ اهليوحت نكمي (DHAP)

ميزنلأ يسكعلا لعافتلا للاخ نم

glycerol phosphate dehydrogenase (

لكشلا رظنا 13

.) DHAP وأ للحت يف كراشت نأ نكمي

ركسلا ثادحتسا .

42

Pathways for production of glycerol phosphate in liver

(DHAP)

• Amino acids: can be degraded except leucine, to form compounds that can be converted to glucose through gluconeogenesis. During starvation, the protein are broken down to provide the amino acids that function as precursors for gluconeogenesis. Some amino acids in the liver are deaminated and the ammonia is excreted in the form of urea.

ركسلا ثادحتسا راسمل ةبسنلاب ةينيملأا ضامحلأل ةيجولويسفلا ةيمهلأا gluconeogenesis

للحتي نأ ةينيملأا ضامحلأل نكمي ءانثتسإب

نيسويللا نيسويلوزيلأاو نوكتل ،

نأ نكمي تابكرم

زوكولج ىلإ لوحتت .

ثيح ةينيمأ ضامحأ ىلا تانيتوربلا رسكتت ،ةعاجملا ءانثأ لمعت

ركسلا ثادحتسلا فئلاسك .

هل ثدحي نأ نكمي دبكلا يف ةينيملأا ضامحلأا ضعب عزن ا

ايرويلا ةروص يف لوبلا يف اينوملأا زرفتو نيملأل .

لاؤس : اذامل نيسويللا نيسويلوزيلأاو ءانثأ

ةعاجملا لالحتي نأ امهنكمي لا -

قاب لثم ضامحلأا ي

ةينيملأا - تابكرم ىلا ىلإ لوحتت نأ نكمي

؟زوكولج .

44

Production of glucose in starvation

45

مقر لكش

14

Fat metabolism in liver during fasting

1. Increased fatty acid oxidation

The oxidation of fatty acids derived from

adipose tissue is the major source of energy in hepatic tissue in the postabsorptive state (see Figure, …..

^③

).

47

Allosteric regulation of malonyl CoA synthesis by acetyl CoA carboxylase. The

carboxyl group contributed by dissolved

CO 2 is shown in blue

Carnitine Shuttle

^:

Is a specialized carrier transports the long-chain acyl group from the cytosol into the mitochondrial matrix. This carrier is rate-limiting transport process called the

carnitine shuttle

49

50

Fat metabolism in liver during fasting

2. Increased synthesis of ketone bodies

• used as fuels by peripheral tissues.

• liver cannot use ketone bodies as a fuel.

• Ketogenesis is favoured when the concentration of acetyl CoA, produced from fatty acid metabolism, exceeds the oxidative capacity of the TCA cycle.

• The availability of circulating ketone bodies is important in fasting because they can be used for fuel by most tissues, including brain tissue.

• Ketogenesis as part of the overall hepatic response to fasting is shown in Figure 16.

•

• ضامحلأا ةينوتيكلا مدختست دوقوك ةطساوب ةجسنلأا ةيفرطلا .

• دبكلا لا نكمي مادختسا ماسجلأا ةينوتيكلا دوقوك .

• لضفيو راسم ديلوت نوتيكلا امدنع نوكي زيكرت ليتيسلاا وك (acetyl CoA)هيا

، يتلا جتنت نم ليثمتلا

يئاذغلا ضامحلأا

،ةينهدلا ةزواجتم ةدئازو ةردقلا ةيدسكأتلا ةرودل سبرك .

• دوجو تانوتيكلا يف ةرودلا ةيومدلا مهم يف ةلاح مايصلا اهنلأ نكمي نأ مدختست دوقوك نم بق ل

مظعم .خملاةجسنأكلذيفامب،ةجسنلأا

• ًامومعو نإف ةيلمع ديلوت نوتيكلا ءزجربتعت نم ةباجتسا دبكلا مايصلل امك وه حضوم يف لكشلا 16 .

51

• Intertissue relationships during

starvation

Fuel sources used by the brain to meet energy needs.

53

• What is Bifunctional enzyme (BFE):

6-phosphofructo-2-kinase/fructose-2,6-

bisphosphatase? What its role in metabolism in liver?

• what is the metabolism of protein during fasting in the liver?

54

رابتخلإا سماخلا

• Draw Cori cycle with illustration all components?

• Why leucine and isoleucine can not working in gluconeogenesis?

• Answer one from the two questions:

– Glycerol as precursor during gluconeogenesis?

– Increased fatty acid oxidation in fat metabolism in liver during fasting?

55