Uncoupling protein and nonalcoholic fatty liver disease
1
Xi JIN, 1Zun XIANG, 1Yi Peng CHEN, 2Kui Fen MA, 3Yue Fang YE, 1You Ming LI*
1
Department of Gastroenterology, The First Affiliated Hospital, College of Medicine,
Zhejiang University, Hangzhou, Zhejiang Province, China
2
Department of Pharmacy, The First Affiliated Hospital, College of Medicine,
Zhejiang University, Hangzhou, Zhejiang Province, China
3
Department of Gastroenterology, The Affiliated Hospital, College of Medicine,
Hangzhou Normal University, Hangzhou, Zhejiang Province, China
Running Title: UCP and NAFLD
* Correspondence to: You Ming LI
Department of Gastroenterology, The First Affiliated Hospital, College of Medicine,
Zhejiang University, Hangzhou, Zhejiang Province, China
No.79 Qing chun Road, Hangzhou, Zhejiang 310003, P.R.China
Fax: 86-571-87236611
Tel: 86-571-87236618
Email: [email protected]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has been widely investigated for its
increasing prevalence but unknown pathogenesis. Currently, under the frame of “two
hit hypothesis”, accumulating evidences supported the importance of mitochondrial
dysfunction, where uncoupling protein (UCP) showed a vital role for uncoupling of
oxidative phosphorylation. Therefore, we here summarized the typical concepts, up to
date findings and existing controversies of UCP2 in NAFLD. We also presented the
novel effect of hepatocellular down regulated mitochondrial carrier protein (HDMCP)
in NAFLD and the new concept that any mitochondrial inner membrane carrier
protein has, more or less, uncoupling ability. Considering the importance of NAFLD
in clinics and UCP in energy metabolism, we believe this review may raise research
enthusiasm on the effect of UCP in NAFLD and provide novel mechanism and
therapeutic target for NAFLD.
Key word nonalcoholic fatty liver disease, uncoupling protein, phosphorylation,
hepatocellular down regulated mitochondrial carrier protein
Introduction
Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease with
hepatocellular lipid deposition and/or ensuing inflammation on the basis of precluding
other known causes. NAFLD has been considered as hepatic manifestation of
metabolic syndrome and consists of progressive stages, ranging from simple steatosis
to nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis(1). With social
development and lifestyle change, NAFLD has now become one of the major causes
of end stage liver diseases (2), with approximate 20% global prevalence. Currently, the
mechanism of NAFLD is still unclear. On the basis of “two hit hypothesis” from Day
CP(3), accumulating data supported the involvement of mitochondrial dysfunction in
NAFLD progress(4), where change of uncoupling protein (UCP) has been intensively
investigated. In this review, we summarized the up to date concept of UCP and its role
in NAFLD progress.
Concept, structure, distribution and biological function of UCP
The concept of oxidative phosphorylation was first proposed in 1961 by Dr.
Mitchell, P(5). In his theory, electrons produced from metabolism are donated to the
electron transport chain (ETC) by nicotinamide adenine dinucleotide-reduced (NADH)
and succinate and further pass along ETC to ultimately reduce molecular oxygen to
water at cytochrome c oxidase. This reaction provides energy for the outward
translocation of protons from the mitochondrial matrix into the inner membrane space
to create an electrochemical gradient across the inner membrane. This gradient then
drives ATP synthesis through the controlled return of protons into the matrix.
However, disconnection of ATP synthesis from mitochondrial respiration exists in
various tissues. Such process is termed as uncoupling of oxidative phosphorylation
and UCP is named for its uncoupling activity (6). UCP belongs to mitochondrial anion
carrier protein family, locates in mitochondrial inner membrane and composes of 6
α-helical type transmembrane units. The C and N termini of UCP are both located at
mitochondrial outer membrane. It is presumed that certain amino acids in the termini
may form the functional part of UCP(7).
Currently, five classical UCPs have been identified in mammals (Table 1), where
UCP 1-3 show high similarity in sequence. UCPs exert their function in the form of
dimmers, with molecular weight ranging between 31 and 34 kDa. Though UCP1
uncoupled energy is used for heat production in brown fat tissue, the physiological
function other UCPs and their regulators are still vague
(8)
. There are two major
hypotheses of UCP1 activation by free fatty acid (FFA)(9-11). One is proton buffering
model, where FFA acts as proton complement that helps to present proton to the
transportation channel. The other is FFA circulation model. In detail, FFA is only able
to pass through mitochondrial inner membrane through UCP1 in mitochondrial matrix.
After binding proton, FFA can “flip-flop” back to the matrix and enter the next
circulation after releasing proton. Besides, accumulating evidences revealed that ATP,
ADP, GTP and GDP can bind to UCP1 with high affinity and reduce its uncoupling
velocity(12). In addition, oxidative radical and superoxide may indirectly regulate
proton leak through metabolic intermediate Hydroxynonenal (HNE) (13, 14).
UCP2 and NAFLD
Among UCPs, UCP2 locates close to genes related with energy metabolism and
obesity
(15)
. Previous studies showed a positive correlation between UCP2 and
obesity(16). Since NAFLD is also associated with obesity and energy surplus, it is
plausible that UCP2 is involved in NAFLD pathogenesis and development. Nowadays,
the effect of UCP2 in NAFLD has been widely investigated and we established a
model (Figure 1) based on accumulated novel findings as followings: Increased FFA
from dietary fat, the adipose tissue and de novo synthesis are available in NAFLD.
They can be taken up into mitochondria mainly through carnitine palmitoyltransferase
1 (CPT1) for β-oxidation, yielding ketons, or fully oxidized within the tricarboxylic
acid cycle (TCA) as well as providing excess NADH and FADH2 that donate
electrons to ETC. UCP2 is then increased and its mediated proton leak also enhanced
in fuel surplus in NAFLD, which on one hand, supports ongoing FFA oxidation and
decreases triglyceride deposition through ATP depletion. On the other hand, increased
UCP2 may decrease △ψm that is the result of proton translocation from mitochondrial
matrix into intermembrane space by ETC and consumed through oxidative
phosphorylation mediated by ATP synthase and through proton leak mediated by
UCP2. The rate of Hydrogen Peroxide (H2O2) production, a vital step in the progress
from steatosis to NASH, is also decreased. In the followings, we will describe detailed
mechanisms of UCP2 in different stages of NAFLD based on “two hit hypothesis”.
Figure 1, Model of UCP2 in NAFLD progress
UCP2 and “the first hit” in NAFLD
In the process of “the first hit”, hyperlipidemia, insulin resistance and other factors
caused hepatic lipid accumulation. The early report on the association between UCP2
and lipid metabolism came from Dr. Fleury, where UCP2 level from white fat tissue
of rat fed with high fat diet was 4-6 times higher than that from normal diet(15).
Besides, hepatocellular UCP2 expression is undetectable under normal physiological
condition but significantly increased in NAFLD, indicating its potential role in disease
development(17-20). Interestingly, the composition of fatty acid influence its ability in
inducing UCP2 expression, where polyunsaturated fatty acid is higher than oligomeric
unsaturated fatty acid(21). Such regulation may be through direct or indirect effect of
transcription factor. For instance, high fat diet or fenofibrate is able to increase UCP2
level of rat by activating peroxide proliferator activator receptor α (PPARα)(22) while
PPARγ ligand is able to induce UCP2 expression and increase lipid accumulation in
fatty liver(23). Further more, resent study showed up-regulation of UCP2 may prevent
NAFLD development (24).
Though increased UCP2 was found in NAFLD, its real effect is still unclear. On
one hand, over produced NADH from mitochondrial FFA β oxidation needs further
oxidation by mitochondrial respiration. However, under the status of energy surplus,
mitochondrial respiration may be hampered by high proton level while UCP2 induced
proton leak is able to decrease mitochondrial membrane potential and thus support
FFA oxidation instead of accumulation. On the other hand, FFA enters mitochondrial
matrix in the form of Acetyl CoA while insufficient NADH re-oxidation may cause
more Acetyl CoA transforming into nonesterifed fatty acid (NEFA). NEFA can’t be
further metabolized in matrix and will then be transported to cytoplasm(25-27). It is
noticeable that FFA accumulation is more harmful than triglyceride accumulation for
inducing cell apoptosis(28). Therefore, UCP2 may also exert as a specific transporter of
metabolite to avoid NEFA accumulation caused damage on mitochondrial matrix.
The effect of UCP2 is also associated with AMPK, an important protein in
phosphorylation and metabolism regulation. In hepatocyte, AMPK alleviates hepatic
lipid accumulation and insulin resistance by increasing FFA oxidation and ketone
formation as well as inhibiting hepatic glyceride and cholesterol synthesis(29). Further
evidence revealed that UCP2 expression was paralleled with AMPK activity(30).
Previous research indicated that UCP2 deficiency caused hepatic lipid accumulation
in a non-insulin dependent manner(31). Interestingly, another report demonstrated that
obesity-related fatty liver is unchanged in mice deficient for mitochondrial UCP2(32).
Furthermore, it was indicated that down-regulation of UCP2 can promote the recovery
of hepatic steatosis (33). These contradictory findings raised discussion on the real
effect of UCP2 on NAFLD. Scientists are eager to know whether UCP2 is protective
in hepatic lipid accumulation in NAFLD. In addition, what is the degree of protection
if the answer is “Yes”. Moreover, are there any other hepatic mitochondrial proteins
having uncoupling activity and involved in NAFLD?
UCP2 and “the second hit” in NAFLD
In the process of “the second hit”, various factors including TNF-α caused liver
inflammatory cell infiltration and abnormal liver function on the basis of hepatic
steatosis. In this process, reactive oxygen species (ROS) produced from mitochondrial
respiration plays a vital role. Theoretically, UCP is involved in the “second hit” for its
ability in regulating mitochondrial respiration. In NAFLD, overloaded FFA in
mitochondrion will increase ROS production and provide soil for ensuing oxidative
reaction. Therefore, it is plausible that UCP2 expression is increased in lipid
accumulated liver to decrease stress from reactive oxidation as an adaptive reaction.
Nevertheless, previous reports indicated that oxidative stress is persistent under the
status of increased hepatic UCP2 expression in rodents(34, 35). Furthermore, the UCP2
level in NASH patients is still unknown and we postulate that increased hepatic UCP2
is insufficient to control ROS production from fat overloaded hepatocyte.
Under normal physiological status, UCP2 is mainly expressed in hepatic kupffer
cell and is undetectable in hepatocytes(36). However, this phenomenon is changed
under specific metabolic status. For instance, UCP2 level is decreased in peripheral
macrophage and mitochondrial ROS production is significantly increased(37). In
addition, endotoxin induced UCP2 expression in hepatocyte and kupffer cell is varied
in UCP2-/- mice receiving macrophage from UCP2+/+ mice through bone marrow
transplantation(38). Therefore, the influence of UCP2 on ROS production in NASH
patients may be resulted from its over expression in hepatocyte and down expression
in kupffer cell.
The negative regulation of UCP2 in hepatic kupffer cell is still vague. Previous
research indicated that UCP2 over expression may be caused by site mutation in a
conserved segment encoding 36 amino acids of exon 2 of UCP2(39). In addition, novel
findings demonstrated that SP1(40), miRNA-15a(41) and PPARα(42) were also able to
regulate UCP2 expression, indicating the complexity of UCP2 regulation network.
Though decreased UCP2 expression in hepatic kupffer cell may cause mitochondrial
ROS production in NASH, the UCP2 over expression in fat accumulated hepatocyte
may also lead to ATP depletion and energy insufficiency, resulting in disease
progression(43). Therefore, we should consider the cell-specific expression character of
UCP2 when concerning it as therapeutic target in NASH.
HDMCP, other UCP and NAFLD
Since UCP2 expression in NAFLD is still in controversy, searching other candidate
UCP has attracted wide attention. In the year of 2004, hepatocellular down-regulated
mitochondrial carrier protein (HDMCP) was cloned by Tan MG and colleagues(44).
HDMCP has basic characters of mitochondrial carrier protein and is exclusively
expressed in liver, with high similarity of protein sequence and gene location among
human, rat and mice. It is able to decrease mitochondrial membrane potential and ATP
production. Therefore, the authors postulated that HDMCP was one of the hepatic
specific UCPs. We further confirmed the GDP insensitive uncoupling ability of
HDMCP in yeast expression system. Since HDMCP is exclusively expressed in liver,
we postulated that it may be associated with NAFLD development and found
increased HDMCP in NAFLD rat model. Furthermore, in NAFLD cell model, we
found HDMCP was able to alleviate lipid accumulation in L02 and HepG2 cells by
decreasing ATP and H2O2 levels(45). Now, researches on HDMCP function have been
carried out in our lab, including: HDMCP level in human; the bilateral effect between
HDMCP and UCP2 in NAFLD; the activator and inhibitor of HDMCP; the role of
HDMCP in NASH and the effect of targeting it for therapeutic purpose.
Liver is the largest metabolic organ in human and the oxygen consumption caused
by proton leak is of 20%-30% total oxygen consumption in resting hepatocytes(46).
According to our knowledge, UCP1 is exclusively expressed in brown fat while the
expression of UCP3-5 in liver has not been reported. Though significantly increased
in NAFLD, UCP2 level is very low in hepatocytes under physiologic status. Therefore,
there might be other proteins with uncoupling ability, where the newly discovered
HDMCP is a good example. Currently, many scientists agreed that any mitochondrial
inner membrane carrier protein has, more or less, the uncoupling ability(45), which
may expand the extent of UCP. Under this conception, we may focus on other
mitochondrial inner membrane carrier protein by testing their uncoupling activity and
role in NAFLD.
Conclusion
NAFLD has been widely investigated for its increasing prevalence but unknown
pathogenesis. Currently, under the frame of “two hit hypothesis”, accumulating
evidences supported the importance of mitochondrial dysfunction in NAFLD, where
UCP showed a vital role for its uncoupling of oxidative phosphorylation. In NAFLD,
UCP2 is intensively studied but results are in controversy. For instance, UCP2 level is
increased in hepatocyte but decreased in kupffer cell in NAFLD. Nevertheless, UCP2
knockout did not influence lipid accumulation in ob/ob mice. HDMCP is a newly
cloned hepatic UCP and a good example for the concept that any mitochondrial inner
membrane carrier protein has, more or less, the uncoupling ability. We further found
that HDMCP was increased in NAFLD and had protective role in lipid accumulation
by decreasing ATP and H2O2 levels. All in all, UCP is closely associated with the
pathogenesis of NAFLD and researches on the effect of UCP in NAFLD may provide
novel mechanisms and therapeutic targets.
Acknowledgement
This review was supported by National Natural Science Foundation of China
(81000169 to Dr. Xi JIN as youth project and 81230012 to Prof. You Ming LI as key
project).
Reference
1 Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002; 346: 1221-31.
2Williams R. Global challenges in liver disease.Hepatology2006; 44: 521-26.
3 Day CP, James OF. Steatohepatitis: a tale of two "hits"? Gastroenterology 1998; 114:
842-45.
4 Dominique Pessayre. Role of mitochondria in non-alcoholic fatty liver disease. J
Gastroentero and Hepatol 2007; 22: Supple 1: S20-S27.
5 Mitchell P. Coupling of phosphorylation to electron and hydrogen transfer by a
chemi-osmotic type of mechanism. Naturwissenschaften 1961; 191:144-48.
6 Stuart JA., Cadenas S., Jekabsons MB., Roussel D, Brand, MD. Mitochondrial
proton leak and the uncoupling protein 1 homologues. Biochim Biophys Acta 2001;
1504:144-58.
7 elMoualij B, Duyckaerts C, Lamotte-Brasseur J. Phylogenetic classification of the
mitochondrial carrier family of Saccharomyces cerevisiae. Yeast 1997; 13: 573-81.
8 Bouillaud F, Couplan E, Pecqueur C,Ricquier D. Homologues of the uncoupling
protein from brown adipose tissue (UCP1): UCP2, UCP3, BMCP1 and UCP4.
Biochim Biophys Acta 2001; 1504:107-19.
9 Winkler E, Klingenberg M. Effect of fatty acids on H+ transport activity of the
reconstituted uncoupling protein. J Biol Chem 1994; 269:2508-15.
10 Skulachev VP. Fatty acid circuit as a physiological mechanism of uncoupling of
oxidative phosphorylation. FEBS Lett 1991; 294:158-62.
11 Jezek P, Orosz DE, Modriansky M, Garlid KD. Transport of anions and protons by
the mitochondrial uncoupling protein and its regulation by nucleotides and fatty acids.
A new look at old hypotheses. J Biol Chem 1994;269: 26184-90.
12 Modriansky M, Murdza-Inglis DL, Patel HV, Freeman KB, Garlid KD.
Identification by site-directed mutagenesis of three arginines in uncoupling protein
that are essential for nucleotide binding and inhibition. J Biol Chem 1997; 272:
24759-62.
13 Negre-Salvayre A, Hirtz C, Carrera G, et al. A role for uncoupling protein-2 as a
regulator of mitochondrial hydrogen peroxide generation. FASEB J 1997;11:809-15.
14 Murphy MP, Echtay KS, Blaikie FH, et al. Superoxide activates uncoupling
proteins by generating carbon-centered radicals and initiating lipid peroxidation:
studies using a mitochondria-targeted spin trap derived from alpha-phenyl-N-tertbutylnitrone. J Biol Chem 2003; 278:48534-45.
15 Fleury C, Neverova M, Collins S, et al. Uncoupling protein-2: a novel gene linked
to obesity and hyperinsulinemia. Nat Genet 1997; 15: 269-72.
16 Esterbauer H, Schneitler C, Oberkofler H, et al. A common polymorphism in the
promoter of UCP2 is associated with decreased risk of obesity in middle-aged humans.
Nat Genet 2001; 28:178-83.
17 Chavin KD, Yang S, Lin HZ, et al. Obesity induces expression of uncoupling
protein-2 in hepatocytes and promotes liver ATP depletion. J Biol Chem1999; 274:
5692-700.
18 Rashid A, Wu TC, Huang CC, et al. Mitochondrial proteins that regulate apoptosis
and necrosis are induced in mouse fatty liver. Hepatology 1999; 29:1131-38.
19 Baffy G, Zhang CY, Glickman JN, Lowell BB. Obesity-related fatty liver is
unchanged in mice deficient for mitochondrial uncoupling protein 2. Hepatology
2002; 35:753-61.
20 Starkel P, Sempoux C, Leclercq I, et al. Oxidative stress, KLF6 and transforming
growth factor-beta up-regulation differentiate non-alcoholic steatohepatitis
progressing to fibrosis from uncomplicated steatosis in rats. J Hepatol 2003;39:
538-46.
21Armstrong MB, Towle HC. Polyunsaturated fatty acids stimulate hepatic UCP-2
expression via a PPAR alpha-mediated pathway. Am J Physiol Endocrinol Metab
2001; 281: E1197-204.
22 Nakatani T, Tsuboyama-Kasaoka N, Takahashi M, Miura S, Ezaki O. Mechanism
for peroxisome proliferator-activated receptor-alpha activator- induced upregulation
of UCP2 mRNA in rodent hepatocytes. J Biol Chem2002; 277:9562-69.
23 Rahimian R, Masih-Khan E, Lo M, van Breemen C, McManus BM, Dube GP
Hepatic overexpression of peroxisome proliferator activated receptorgamma2 in the
ob/ob mouse model of non-insulin dependent diabetes mellitus. Mol Cell Biochem
2001; 224: 29-37.
24 Poulsen MM, Larsen J, Hamilton-Dutoit S, Clasen BF, Jessen N, Paulsen SK, et al.
Resveratrol up-regulates hepatic uncoupling protein 2 and prevents development of
nonalcoholic fatty liver disease in rats fed a high-fat diet. Nutr Res. 2012. 32(9):
701-8.
25 Nobes, CD, Hay WW Jr, Brand MD. The mechanism of stimulation of respiration
by fatty acids in isolated hepatocytes. J Biol Chem1990; 265: 12910-15.
26 Eaton, S. Control of mitochondrial beta-oxidation flux. Prog Lipid Res 2002;
41:197-239
27 Hunt MC, Alexson SE. The role Acyl-CoA thioesterases play in mediating
intracellular lipid metabolism. Prog Lipid Res 2002; 41: 99-130
28 Listenberger LL, Han X, Lewis SE, et al. Triglyceride accumulation protects
against fatty acid-induced lipotoxicity. Proc Natl Acad Sci USA 2003; 100:3077-82.
29 Carling D. The AMP-activated protein kinase cascade-a unifying system for
energy control. Trends Biochem Sci 2004; 29:18-24.
30 Song S. Uncoupling protein-2: Evidence for its function as a metabolic regulator.
Diabetologia 2003, 46:132-33.
31 Fulop P, Wands JR, Baffy G: UCP2 affects fasting induced steatosis and metabolic
parameters in lean and obese mice. Hepatology 2002; 36:413A.
32 Baffy G, Zhang CY, Glickman JN, Lowell BB Obesity-related fatty liver is
unchanged in mice deficient for mitochondrial uncoupling protein 2. Hepatology 2002;
35:753-61.
33 Yang QH, Hu SP, Zhang YP, Xie WN, Li N, Ji GY, et al. Effect of berberine on
expression of uncoupling protein-2 mRNA and protein in hepatic tissue of nonalcoholic fatty liver disease in rats. Chin J Integr Med. 2011; 17(3):205-11.
34 Yang S, Zhu H, Li Y, et al. Mitochondrial adaptations to obesity-related oxidant
stress. Arch Biochem Biophys 2000; 378: 259-68.
35 Soltys K, Dikdan G, Koneru B. Oxidative stress in fatty livers of obese Zucker rats:
rapid amelioration and improved tolerance to warm ischemia with tocopherol.
Hepatology 2001; 34:13-18.
36 Larrouy D, Laharrague P, Carrera G, et al. Kupffer cells are a dominant site of
uncoupling protein 2 expression in rat liver. Biochem Biophys Res Commun 1997, 235:
760-64.
37 Lee FY, LiY, Yang EK, et al. Phenotypic abnormalities in macrophages from
leptin deficient, obese mice. Am J Physiol1999; 276:C386-94.
38 Alves-Guerra MC, Rousset S, Pecqueur C, et al. Bone marrow transplantation
reveals the in vivo expression of the mitochondrial uncoupling protein 2 in immune
and nonimmune cells during inflammation. J Biol Chem 2003; 278:42307-12.
39 Pecqueur C, Alves-Guerra MC, Gelly C, et al. Uncoupling protein 2, in vivo
distribution, induction upon oxidative stress, and evidence for translational regulation.
J Biol Chem2001;276: 8705-12.
40 Jiang Y, Zhang H, Dong LY, Wang D, An W. Increased hepatic UCP2 expression
in rats with nonalcoholic steatohepatitis is associated with upregulation of Sp1
binding to its motif within the proximal promoter region. J Cell Biochem 2008;
105:277-89.
41 Sun LL, Jiang BG, Li WT, Zou JJ, Shi YQ, Liu ZM. MicroRNA-15a positively
regulates insulin synthesis by inhibiting uncoupling protein-2 expression. Diabetes
Res Clin Pract 2011; 91: 94-100.
42 Andrew D Patterson, Yatrik M Shah, Tsutomu Matsubara, Kristopher W Krausz,
Frank J Gonzalez. Peroxisome proliferator-associated receptor alpha induction of
uncoupling protein 2 protects against acetaminophen-induced liver toxicity.
Hepatology 2012; 56: 281-90.
43 Yang SQ, Lin HZ, Lane MD, Clemens M, Diehl AM. Obesity increases sensitivity
to endotoxin liver injury: implications for the pathogenesis of steatohepatitis. Proc
Natl Acad Sci U S A 1999; 94:2557-62
44 Tan MG, Ooi LL, Aw SE, Hui KM. Cloning and identification of hepatocellular
carcinoma down-regulated mitochondrial carrier protein, a novel liver-specific
uncoupling protein. J Biol Chem 2004; 279:45235-44.
45 Jin X, Yang YD, Chen K, et al HDMCP uncouples yeast mitochondrial respiration
and alleviates steatosis in L02 and HepG2 cells by decreasing ATP and H2O2 levels, a
novel mechanism for NAFLD. J Hepatol 2009; 50: 1019-28.
46 Brand MD. The proton leak across the mitochondrial inner membrane. Biochim
Biophys Acta 1990; 1018:128-33.
47 Cioffi F, Sense R, de Lange P, Goglia F, Lanni A, Lombardi A. Uncoupling
proteins: a complex journey to function discovery. Biofactors.2009; 35: 417-28.
Table
Table 1, Allocation and Distribution of UCP
Gene
Allocation
Distribution
UCP1
mice chromosome 8，human chromosome4q31
Only in brown fat tissue
UCP2
ratchromosome 7, human chromosome11q13
various tissue
UCP3
ratchromosome 7, human chromosome 11q13
bone and heart tissue
UCP4
human chromosome6pl1.2 - q12
brain tissue
UCP5
human chromosome Xq24
brain and tonsil