SREBP

&
NAFLD
 Introduction
 Sterol reglatory element bindin g protein are family of trnscription factors

that regulate hepatocyte cholesterol regulation and homeostasis.

 Activate exprssion of more than 30 gene involved in regulation, synthesis

& homeostasis (triacylglycerols, phospholipids, cholesterol, and, free fatty

acids).
 The SREBPs are three-domain proteins bound to membranes of the
endoplasmic reticulum (ER) and nuclear envelope in a hairpin orientation
(Osborne T F., 2000)

Ahmed MH et al., 2007

 Location and function of different isoforms of SREBP s ( Ferre P et al., 2007)

SREBP 1 SREBP2

SREBP1a SREBP1c

Location spleen & intestine. Adult adipocytes and Vascular endothelials

Liver

Function lipogenesis, fatty acid metabolism cholesterol homeostasis

expression Expression Expression stimulated Expression stimulated by

stimulated by by nutrition, glucose, cholesterol depletion
cholesterol depletion insulin
 SREBP maturation
(Goldstein JL et al., 2002. Brown M S et al., 1999)

 Immediately after their synthesis on ER membranes, the SREBPs bind to

Scap through an interaction between the COOH-terminal regulatory domain

of the SREBP and the cytosolically-oriented COOH-terminal domain of
Scap (Goldstein JL., etal.,2005). SCAP also bind with Cop II protein.

INSIG SREBP
SCAP
ER-lumen

C N
Scap contain 2 domain:
•NH2-terminal membrane attachment domain, with eight transmembrane (TM)
helices separated by hydrophilic loops. Helices 2–6 comprise the sterol-sensing
domain.
•COOH terminal domain which bind with COOH terminal domain of SREBPs
 In cholesterol depleted cells: Conformation of SCAP is altered due alteration in

conformation of SSD (sterol sensitive domain) in cholesterol depletion:

INSIG SCAP SREBP

ER lumen

C N
  In cholesterol depleted cells

– Conformational change of SCAP in SSD (sterol sensitive domaine)

enables the dissociation of INSIG from SCAP

SREbp
INSIG
SCAP
ER-lumen

C N
  Cluster of SCAP/SREBP complex binds with COP II protein and in to coated a

vesicle bud from ER and travel to golgi complex.

Golgi-lumen SCAP SREBP

C N
 SREBP is cleaved in the Golgi apparatus

 In Golgi apparatus SREBP is sequentially cleaved by two membrane bound

proteases in process called regulated intra membrane proteolysis.(Yang t. et al.,

2002)
 Site-1 protease (S1P) and Site-2 protease (S2P), respectively

 S1P is a serine protease

 S2P is a zinc metalloproteinase

Golgi-lumen
S1P
SCAP SREBP

C N
 S1P is cholesterol sensitive - low cholesterol content --> cleavage by

S1P, followed by S2P cleavage

Golgi-lumen
S1P
SCAP SREBP
S2P

C N
 SREBP is cleaved in the Golgi apparatus

 These clevage release NH2 terminal segment SREBP so that it can

enter nucleus.

Golgi-lumen
S1P
SCAP SREBP
S2P

N
C
Summary of SREBP maturation
C

Nucleus
CHOLESTEROL
N

ER Golgi
C

C
C
65 kB
N
125 kB
N
 Function of SREBP
 Insulin regulate hepatic glucose level by inhibiting glucose production and

stimulating glycogenesis.
 Once glycogen store is replenished glucose enter glycolytic pathway and

thereby de novo lipogenesis.

 Insulin a anabolic hormone promote triglyceride synthesis and inhibit FFA

oxidation.
 Insulin’s action in modulating lipid- glucose homeostasis is regulated by

SREBPs.
 Insulin and SREBPs stimulate key lipogenic enzymes, as ACC, FAS.

Ferre P et al., 2007; Ahmed MH et al., 2007

  SREBP acts in synergy with ChREBP and induce glycolytoc and lipogenic
enzymes

Glucose Glucose 6- phosphate Glyceraldehyde 3-

phosphate

Glucokinase

SREBP 1c Phosphoenol pyruvate

ChREBP

L-Puruvate Kinase Pyruvate

SREBP 1c

Ahmed MH et al., 2007

 SREBPs and its Association with NAFLD
 Non alcoholcic fatty liver disease is a condition of accumulation of fat in liver(>5% of

liver weight) in individual who drinks alcohol with in safe limit.

 NAFLD is commonly associated with insulin resistance and obesity.

Ferre P et al., 2007

 Proof of Concept
 SREBP-1c levels are elevated in the fatty livers of obese, insulin-resistant and

hyperinsulinaemic ob / ob mice (Shimomura I et al., 2006; Shimomura I et al.,

1999).
 Conerello SL etal in 2003 shows that DPP IV knock out mice are protected

against obesity and insulin resistance and also SREBP-1c expression reduced
in these mice.
 On the othe other hand it has been found that DPP IV is elevated in NAFLD

patients and which is directly proportional with grade of steatosis (Firneisz G

et al.,2009; Balban et al., 2007; Yilmaz et al., 2009).
 So it is assummed DPP IV may have role in expression of SREBP1c.
 Conclusion
It can be hypothesized from the above discussion that DPP IV inhibitor
may down regulate SREBP 1c expression and may be effective in
treatment of steatosis
Thank You
 Three SREBP isoforms are there: SREBP1a, SREBP1c, SREBP 2.

 SREBP 1 is involved in de-novo lipogenesis, fatty acid metabolism where

SREBP2 regularte cholesterol homeostasis.

 SREBP 1a is expressed in tissues with high capacity of cell proliferation

such as spleen & intestine.

 SREBP 1c predominant in liver and adipocytes.

 After their translation in ER membrane SREBPs bind with SREBP clevage

activating protein, polytopic membrane protein.