8/9/2019 Regulation of Lipids

1/13

REGULATION OF LIPIDS

NAME AAKRITI SHARMA

CLASS BBT -2

ROLL NO BBT-2-08038

8/9/2019 Regulation of Lipids

2/13

Fatty acids are an impo rtant sou rce of energy for m any o rgan isms. Ex ce ss glucos e can be sto red efficiently as f at . Triglycer ide s yield mo re than tw ice as mu ch energy for the sam e m assas do car bo hydrate s o r pro te ins. All cell m emb rane s are bui lt up of phosp ho lipids

, each of

wh ich conta ins tw o f atty ac ids. Fatty ac ids are also us ed for p ro te in mo d ificat ion . The m eta bo lism of f atty ac ids, there fo re , consists of cata bo lic p roce sse s wh ich generate energy and primary m eta bo lite s f rom f atty ac ids, and ana bo lic proce sses wh ich create bio logically impo rtant mo lecu les f rom f atty ac ids and o ther d ietary car bo n sou rce s.

Lipolysis is carr ied ou t by lipase s.Once f reed f rom glycer o l

, f ree f atty ac ids can enter b loo d and mus cle fiber by d iffusio n .Beta oxidat ion sp lits long car bo n cha ins of the f atty ac id int o acetyl CoA

, wh ich can event ually enter the TCAcycle .Brief ly, -oxi dat ion o r lipo lysis of f ree f atty ac ids is as fo llows:Dehydr ogenat ion by acyl -CoA dehydr ogena se

, yield ing 1 FADH2Hydrat ion by en oyl-CoA hydrata se

Dehydr ogenat ion by 3-hydr oxyacyl -CoA dehydr ogena se

, yield ing 1 NADHCleavage by th io lase , yield ing 1 acetyl -CoA and a f atty ac id that ha s now been sho rtened by 2 car bo ns (acyl -CoA)Th is cycle re peat s u nt il the FFA ha s b een comp letely red uced to acetyl -CoA o r, in the case

of f atty ac ids w ith odd numb er s of car bo n at oms, acetyl -CoA and 1 mo l of propio nyl-CoAper mo l of f atty ac id .

Overv iew

8/9/2019 Regulation of Lipids

3/13

Regul ation and cont ro lIt ha s long been held that ho rmo ne -sen sit ive lipase (HSL) is the enzy m e that hydr o lyse s

tr iacylglycer ide s to f ree f atty ac ids f rom f at s ( lipo lysis). Ho wever , mo re recently it ha s b een shown that at mos t HSLconvert s tr iacylglycer ide s to mo noglycer ide s and f ree f atty ac ids.Mo noglycer ide s are hydr o lyzed by mo noglycer ide lipase; ad ipos e tr iglycer ide lipase m ay have a sp ec ial ro le in convert ing tr iacylglycer ide s to d iacylglycer ide s, wh ile d iacylglycer ide sare the be st subs trate for HSL.. HSL is reg u lated by the ho rmo ne s insu lin , glucag on

,no re pine phr ine

, and epine phr ine .

Glucag on is asso ciated w ith low b loo d glucos e , and epine phr ine is asso ciated with increa sed m eta bo lic de m and s. In bo th situat ions, energy is needed , and the oxidat ion of f atty ac ids is increa sed to m eet that need . Glucag on , no re pine phr ine , and epine phr ine bind to G p ro te in-coup led rece p to rs wh ich act ivate adenylate cycla se to p roduce cyclic AMP.cAMP conseq uently act ivate s p ro te in kina se A, wh ich phosp ho rylate s ( and act ivate s)ho rmo ne -sen sit ive lipase .When b loo d glucos e is h igh , lipo lysis is i nh ibited by insu lin . Insu lin act ivate s pro te in phosp hata se 2A, wh ich de phosp ho rylate s HSL, there by inh ibit ing its act ivity. Insu lin alsoact ivate s the enzy m e phosp hod ie stera se

, wh ich brea ks down cAMP and stops the re -phosp ho rylat ion eff ect s of p ro te in kina se A.For the reg u lat ion and contr o l of m eta bo lic react ions invo lving f at synthe sis, s ee lipo gene sis .

8/9/2019 Regulation of Lipids

4/13

AMP protein kinase(active)

AMP protein kinase(inactive)

P i+insulin

proteinphosphatase

ATP ADP

ATP

ADPhigh [AMP] P i

high [ATP]

acetyl CoAcarboxylase(monomeric)

LOW ACTIVITY OH

INACTIVE FORM

O P O 3

F igure 1. R egulation of acetyl CoAcarboxylase by glucagon, epinephrine, insulinand AMP

glucagon or epinephrine

viacAMP

protein kinase A

Inhibits proteinphosphatase byphosphorylation

8/9/2019 Regulation of Lipids

5/13

F igure 2. H ormonal activation of triacylglycerol (hormone-sensitive) lipase.H ormone signals from epinephrine or glucagon promote mobilization of fatty acids(lipolysis) via production of cyclic AMP. Activated protein kinase A, phosphorylatesHSL -b to the active HSL -a form .

R E E T R S

ATP

proteinkinase A

cellmembr an e

E pinephrineGlucagon

HORMONES

cyclic AMP

ATP

ADP

= activation- = inhibition

TriacylglycerolFatty acid +

Diacylglycerol

O PHSL-a

protein phosphatase

P i

+Insu lin

- ca ff e ine

P hospho-diesterase

AMP

+

Adenylyl cyclase

(inactive form)

HSL -bOH

inacti veacti ve

+

+insu lin

8/9/2019 Regulation of Lipids

6/13

Ch o le st er o l is a wa xy ster oid m eta bo lite fou nd in the cell m emb rane s and tran spo rted in the b loo d p lasm a of all an imals. It is an e ssent ial str uct ural compo nent of m amm alian cell m emb rane s, where it is req uired to esta b lish p rop er m emb rane per m ea bi lity and f luid ity. In add it ion , ch o lester o l is an impo rtant compo nent for the m an uf act ure of bile ac ids

, ster oid ho rmo ne s, and several f at -so lub le vita mins. Cho lester o l is the p rinc ipal ster o l synthe sized by an imals, bu t sm all quant it ie s are synthe sized in o ther eukary o te s, su ch as p lant s and fung i. It isalmos t comp letely abs ent amo ng prokary o te s

, wh ich include bacter ia .

Cho lester o l

8/9/2019 Regulation of Lipids

7/13

Regul ation of c h o le st er o l Biosynthe sis of cho lester o l is d irectly reg u lated by the cho lester o l level s p re sent , th ou gh the hom eos tat ic m echan isms i nvo lved are only partly under stoo d . A h igher inta ke f rom foo d lead sto a net decrea se in end ogen ous p roduct ion , wherea s lower inta ke f rom foo d ha s the opposi te

e ff ect . The m a in reg u lat o ry m echan ism is the sen sing of intracell u lar cho lester o l in the end op lasmi c ret icu lum by the pro te in SREBP (ster o l reg u lat o ry ele m ent -bind ing p ro te in 1 and 2)

In the pre sence of cho lester o l, SREBP is bou nd to tw o o ther pro te ins: SCAP (SREBP-cleavage -act ivat ing pro te in) . W hen ch o lester o l level s f all, Insig-1 d isso ciate s f rom the SREBP-SCAPcomp lex, allowing the comp lex to mi grate to the Go lgi app arat us , where SREBP is cleaved by

S1P and S2P (si te -1 and -2 p ro tea se ), tw o enzy m es that are act ivated by SCAP when cho lester o l level s are low. The cleaved SREBP then migrate s to the nucleus and act s as a tran scr ipt ion f act o r to bi nd to the SRE (ster o l reg u lat o ry ele m ent ), wh ich st imu late s the tran scr ipt ion of m any gene s. Amo ng the se are the LDLrece p to r and HMG-CoA red ucta se . The fo rm er scavenge s circu lat ing LDL f rom the b loo dstrea m, wherea s HMG-CoA red ucta se lead s toan increa se of end ogen ous p roduct ion of cho lester o l.[18] A large part of th is signal ing pathway wa s clar ified by Dr. Michael S. Brown and Dr. Jos eph L. Goldste in in the 1970s. I n 1985, they rece ived the Nob el Prize in Physio logy o r Med icine for the ir wo rk. The ir subs eq uent wo rkshows how the SREBP pathway reg u late s expre ssio n of m any gene s that contr o l lipid form at ion and m eta bo lism and bo dy fuel allocat ion .

8/9/2019 Regulation of Lipids

8/13

NUCLEUSENDOPLASMICRETICULUM

HighCholesterol

F igure 3. HMG CoA reductase is induced when intracellular cholesterolbecomes too low while with high cholesterol SREBP is bound to the

endoplasmic reticulum and is thus rendered ineffective

NUCLEUSLowCholesterolENDOPLASMIC

RETICULUM

mRNA for HMG CoAReductase

synthesis of HMGCoA reductase

= SREBP, sterol regulatoryelement binding protein

8/9/2019 Regulation of Lipids

9/13

Tr iglycer id e s

Triglycer ide s, as m ajo r compo nent s of very low den sity lipop ro te in (VLDL)and chylomi crons,

p lay an impo rtant ro le in m eta bo lism as energy sou rce s and tran spo rter s of d ietary f at . They conta in mo re than tw ice as mu ch energy (9 kcal /g o r 38 kJ /g ) as car bo hydrate s and pro te ins.In the inte st ine , tr iglycer ide s are sp lit int o mo noacylglycer o l and f ree f atty ac ids in a p roce sscalled lipo lysis , w ith the secret ion of lipase s and bi le , wh ich are subs eq uently mo ved toabso rp t ive enter ocyte s, cells lin ing the inte st ine s. The tr iglycer ide s are re bui lt in the enter ocyte s f rom the ir f rag m ent s and pac kaged together w ith cho lester o l and pro te ins toform chylomi crons. The se are excreted f rom the cells and co llected by the lymp h syste m and tran spo rted to the large vessels near the heart before be ing mixed int o the b loo d . Var ioust issu es can cap ture the chylomi crons, relea sing the tr iglycer ide s to b e us ed as a sou rce of energy . Fat and liver cells can synthe size and sto re tr iglycer ide s. W hen the bo dy req uire sf atty ac ids as an energy sou rce , the ho rmo ne glucag on signal s the brea kdown of the tr iglycer ide s b y ho rmo ne -sen sit ive lipase to relea se f ree f atty ac ids. As the b ra in cann o t u t ilize f atty ac ids as an energy sou rce (unle ss converted to a ket one ), the glycer o l compo nent

of tr iglycer ide s can be converted int o glucos e , via glucone ogene sis , fo r bra in fuel when it isbroken down . Fat cells m ay also b e broken down for that rea so n , if the b ra in' s need s ever ou twe igh the bo dy' s.Triglycer ide s cann o t pass thr ou gh cell m emb rane s f reely . Sp ec ial enzy m es o n the wall s of b loo d vessels called lipop ro te in lipase s mus t brea k down tr iglycer ide s int o f ree f atty ac idsand glycer o l. Fatty ac ids can then be ta ken up b y cells via the f atty ac id tran spo rter (FAT).

.

8/9/2019 Regulation of Lipids

10/13

Biosynthe sis of T riacylglycer o ls

Triacylglycer o ls are fo rm ed by react ion of tw o mo lec u les of f atty acyl CoA w ith glycer o l3-p hosp hate to fo rm p hosp hat id ic ac id; th is p roduct is de phosp ho rylated to ad iacylglycer o l, then acylated by a th ird mo lecu le of f atty acyl CoA to yield atr iacylglycer o l.

The synthe sis and degradat ion of tr iacylglycer o l are ho rmo nally reg u lated .

Mobi lizat ion and recycl ing of tr iacylglycer o l mo lec u les re su lts in a tr iacylglycer o l cycle .

Triacylglycer o ls are re synthe sized f rom f ree f atty ac ids and glycer o l 3-p hosp hate evenduring starvat ion . The d ihydr oxyacet one phosp hate p rec urso r of glycer o l 3-p hosp hate isder ived f rom p yruvate via glycer one ogene sis.

8/9/2019 Regulation of Lipids

11/13

FIGURE 4. T h e t r iacy lglycer o l cyc le . In m a mm a ls, t r iacy lglycer o l mo lec u les are broken down and re synthe sized in a tr iacylglycer o l cycle during starvat ion . Som e of the f atty ac ids relea sed by lipo lysis of tr iacylglycer o l in ad ipos e t issu e pass int o the b loo dstrea m,

and the re m a inder are us ed fo r re synthe sis of tr iacylglycer o l. Som e of the f atty ac idsrelea sed int o the b loo d are us ed for energy (in mus cle , fo r examp le),and som e are ta ken up b y the liver and us ed in tr iacylglycer o l synthe sis. The tr iacylglycer o l form ed in the liver is tran spo rted in the b loo d bac k to ad ipos e t issu e ,where the f atty ac id is relea sed by extracell u lar lipop ro te in lipase , ta ken up b y ad ipo cyte s, and ree ster ified int o tr iacylglycer o l.

8/9/2019 Regulation of Lipids

12/13

8/9/2019 Regulation of Lipids

13/13

Figure 5. Overv iew of s ynthe sis and m eta bo lism of tr iglycer ide -rich lipop ro te ins. In insu lin-re sistant state s, liver VLDL synthe sis is dr iven by TG content w ith in the he pat ocyte s and cont inue s at h igh rate s du ring the pos tprand ial per iod . DNL f rom d ietary car bo hydrate s, p lasm a FFA poo l and tr iglycer ide -rich lipop ro te in (TRL) upta ke int o the liver all contr ibu te to the liver TGcontent ava ilab le for VLDLassemb ly. Inte st inal chylomi crons carry apoB-48 as the str uct ural apo lipop ro te in . To date , the sm all inte st ine ha s b een considered a passive abso rp t ion site for d ietary f at . Ho wever , the rate of chylomi cron app earance in circu lat ion m ay be de pendent on insu lin sen sit ivity of enter ocyte s as well as the seq uence of dayl ong m eal s. Bo th chylomi cronsand VLDL part icle s exhange apoA, E and C spec ies, TG and cho lesteryl ester s w ith HDL part icle s

in p roce sse s invo lving CETP and PLTP act ivity. There fo re , h igh pos tprand ial TRLlevel s contr ibu te to ather ogen ic change s in HDL. During intrava scu lar lipo lysis b y LPLand he pat ic lipase , TRLsare converted int o h ighly ather ogen ic re m nant part icle s. The se re m nant s are internal ized to the liver via commo n pathway s invo lving LDLR, LDLR-related p ro te in and , mos t prob ab ly HSPG.During pos tprand ial lipo lysis TRL-der ived FFA is sto red in the ad ipos e t issu e , bu t also contr ibu te ssign ificantly to the p lasm a FFA poo l and th us, to liver f at content . Insu lin reg u late s var ious s te ps

in TRL meta bo lism at lea st in the liver , ad ipos e t issu e and also i nte st ine . CE = Cho lesteryl ester; CETP = Cho lesteryl ester tran sf er pro te in; ChREBP = Car bo hydrate re spo nsive ele m ent -bind ing p ro te in; DNL = De novo lipo gene sis ; FA = Fatty ac id; FFA = Free f atty ac id; HSPG = Heparan su lf ate pro te oglycan s; LDLR = LDL-rece p to r; LPL = Lipopro te in lipase; PLTP = Phosp ho lipid tran sf er pro te in; SREBP-1c = Ster o l reg u lat o ry-ele m ent bind ing pro te in 1c; TG = Triglycer ide .