Are hepatic steatosis and carotid intima media thickness associated in obese patients with normal or slightly elevated gamma-glutamyl-transferase?

Tarantino Giovanni, Finelli Carmine, Colao Annamaria, Capone Domenico, Tarantino Marianna, Grimaldi Ernesto, Chianese Donato, Gioia Saverio, Pasanisi Fabrizio, Contaldo Franco, Scopacasa Francesco, Savastano Silvia

Description

Hepatic steatosis (HS) has been associated with obesity and metabolic syndrome (MS), conditions carrying a high risk of coronary artery disease. We aimed to determine whether HS was an independent factor of atherogenic risk beyond its association with MS and its components. Methods We assessed the circulating levels of the heat shock protein-70 (HSP-70), a chaperone involved in inflammation, endoplasmic reticulum stress and apoptosis at liver and endothelial level and the gamma-glutamyl transferase activity (γ-GT) correlating them to carotid intima-media thickness (IMT), along with lipid profile, HOMA, C-reactive protein, fibrinogen, ferritin, adiposity type as well as spleen volume in 52 obese pts with grade 1, 128 with grade 2, and 20 with grade 3 of HS evaluated by sonography. Results Patients with different grade of HS demonstrated overlapping HSP-70 levels; similarly performed obese subjects regarding IMT. Using multiple regression analysis, IMT was predicted by age, visceral adiposity and by HOMA (β = 0.50, p < 0.0001, β = 0.30, p = 0.01 and β = 0.18, p = 0.048 respectively, while the severity of HS was predicted by visceral and subcutaneous adiposity and HOMA (β = 0.50, p < 0.0001 and β = 0.27, p = 0.001 and β = 0.18, p = 0.024, respectively). Conclusion In our series of patients with normal or mild elevation of γ-GT, the severity of HS does not entail higher IMT, which may be linked to MS stigmata.

Sujets

• Non-alcoholic fatty liver disease
• Atherosclerosis
• Metabolic syndrome

Informations

• Publié par: biomed
• Publié le: 01 janvier 2012
• Nombre de lectures: 11
• Langue: English

Extrait

Tarantino et al. Journal of Translational Medicine 2012, 10:50
http://www.translational-medicine.com/content/10/1/50
RESEARCH Open Access
Are hepatic steatosis and carotid intima media
thickness associated in obese patients with
normal or slightly elevated
gamma-glutamyltransferase?
1* 2 3 4 5Giovanni Tarantino , Carmine Finelli , Annamaria Colao , Domenico Capone , Marianna Tarantino ,
6 6 2 1 1 6Ernesto Grimaldi , Donato Chianese , Saverio Gioia , Fabrizio Pasanisi , Franco Contaldo , Francesco Scopacasa
3and Silvia Savastano
Abstract
Background: Hepatic steatosis (HS) has been associated with obesity and metabolic syndrome (MS), conditions
carrying a high risk of coronary artery disease. We aimed to determine whether HS was an independent factor of
atherogenic risk beyond its association with MS and its components.
Methods: We assessed the circulating levels of the heat shock protein-70 (HSP-70), a chaperone involved in
inflammation, endoplasmic reticulum stress and apoptosis at liver and endothelial level and the gamma-glutamyl
transferase activity (g-GT) correlating them to carotid intima-media thickness (IMT), along with lipid profile, HOMA,
C-reactive protein, fibrinogen, ferritin, adiposity type as well as spleen volume in 52 obese pts with grade 1, 128
with grade 2, and 20 with grade 3 of HS evaluated by sonography.
Results: Patients with different grade of HS demonstrated overlapping HSP-70 levels; similarly performed obese
subjects regarding IMT. Using multiple regression analysis, IMT was predicted by age, visceral adiposity and by
HOMA (b = 0.50, p < 0.0001, b = 0.30, p = 0.01 and b = 0.18, p = 0.048 respectively, while the severity of HS was
predicted by visceral and subcutaneous adiposity and HOMA (b = 0.50, p < 0.0001 and b = 0.27, p = 0.001 and
b = 0.18, p = 0.024, respectively).
Conclusion: In our series of patients with normal or mild elevation of g-GT, the severity of HS does not entail
higher IMT, which may be linked to MS stigmata.
Keywords: NAFLD, Atherosclerosis, Metabolic syndrome
Background (IR) and endoplasmic reticulum stress (ERS) [3]. Heat
Unclassified nonalcoholic fatty liver disease (NALFD) or shock proteins (HSPs) function as intra-cellular
chaperhepatic steatosis (HS), a further expression of the meta- ones. The unfolded protein response (UPR), a
fundamenbolic syndrome (MS) [1], easily detected by ultrasound tal cellular process triggered by ERS, is aimed at initiating
(US), is highly prevalent condition in obese individuals. programmed cell death. The UPR is activated and
dysreFree fatty acids (FFAs) have been shown to be the major gulated in NAFLD [4]. On the other hand, chronic ERS
contributor to triglyceride accumulation in hepatocytes activates UPR in arterial endothelium in regions of
susobserved in NAFLD [2]. The excessive supply of FFAs ceptibility to atherosclerosiss [5]. ERS activation
particitoward the liver leads per se to hepatic insulin resistance pates in fat deposition in the liver [6] and could directly
induce IR. Insulin-resistant state in turns increases the
* Correspondence: [e-mail] plasma FFAs flux [7]. The best known member of HSP is
1Department of Clinical and Experimental Medicine, Federico II University the stress-inducible form of HSP-70, i.e., HSP-72, also
Medical School of Naples, Naples, Italy
called HSPA1A. The HSP-70 expression decreases withFull list of author information is available at the end of the article
© 2012 Tarantino et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.Tarantino et al. Journal of Translational Medicine 2012, 10:50 Page 2 of 9
http://www.translational-medicine.com/content/10/1/50
age in humans [8]. Hamsters fed high-fructose diet exhi- Inclusion criteria
bit fat accumulation in liver and the Hsp70 expression is Two hundred obese patients with at least another
criterdown-regulated [9]. These data were confirmed in obese ium of those below specified clustering MS, diagnosed
Zucker rats with HS [10]. Ischemic preconditioning by suffering from NAFLD by evaluating the liver/kidney
increasing HSP-72 protects steatosic livers [11]. In wild- difference of brightness at US, with or without elevated
alanine aminotransferase (ALT) or g-GT, were studied.type mice, refractory to high-fat dietary-induced effects, a
They were allocated in three groups according to themarked increase in HSP-72 levels in liver was evidenced
severity of HS scored at US.[12]. HSP-70 can be produced in the liver and spleen as
Obese individuals were selected to participate in thisacute phase reactant and released into circulation to
facilitate the disposal of dying cells [13]. Low-grade study before being given weight control indications. The
chronic inflammation, which is characterized by degrees of obesity was established on the basis of body
increased serum concentrations of interleukin-6 (IL-6) mass index (BMI) cut-off points of 30-34.9, 35-39.9 and
2and enlarged spleen volume [14] likely due to dendritic >40 kg/m , respectively. Central obesity was identified by
cells (DCs) mobilization, is contributing factor in devel- waist circumference (WC) >102 cm in men or >88 cm in
oping the more severe form of HS in obese patients. women, measured at the midpoint between the lower
HSPs have been reported to play important roles in acti- border of the rib cage and the iliac crest. Presence of type
vation and maturation of DCs [15]. Moreover, the con- 2diabetesmellitus(T2D)wasassessedbyafasting
centration of HSP-70 is inversely correlated to IL-6 [16]. plasma glucose ≥126 mg/dl (≥7.0 mmol/l), confirmed on
Gamma-glutamyltransferase (g-GT) is a subclinical clue a separate day or a random glucose level of 200 mg/dL or
of IR [17], even though the prevailing interpretation is higher and classic symptoms of T2D (polyuria,
polydipthat its high serum levels represent just an early evidence sia, polyphagia, weight loss) or HbA1c ≥6.5%. Impaired
of oxidative stress. Its mechanism relies on the fact that fasting glucose (IFG) was set with a fasting plasma
glucellular g-GT is closely linked to metabolism of glu- cose between 100 and 125 mg/dl. MS was defined
tathione (GSH), the most abundant intracellular antioxi- according to the revised Adults Treatment Panel III
dant [18]. Depletion of GSH affects the synthesis of HSP- (2001), and three or more criteria were considered:
1
70 in Hep G2 cells [19]. Finally, HS is characterized by plasma glucose concentration of at least 100 mg dL- ,
elevated levels of g-GT [20], which is also a predictor of WC >102 cm in men and >88 cm in women, serum
highdensity lipoprotein (HDL)-cholesterol concentrationcoronary artery disease (CAD) [21].
-1 i -1 i<40 mg dL nmenand<50mgdL nwomen,bloodThe direct contribute of HS to early atherosclerosis,
pressure of at least 130/85 mm Hg, and serum triglycer-evaluated as increased intima media thickness (IMT),
-1is controversial. Against this background, we thought ide concentration of at least 150 mg dL . The subjects
of exploring the behavior of HSP-70 and g-GT, mole- were classified as insulin resistant according to a
strincules playing a key role in both liver and endothelium, gent homeostasis model assessment of IR (HOMA)
setin obese patients with different entity of hepatic fat ting the cut-off at 2.
storage in relationship to carotid IMT in order to Exclusioncriteriawereahistory of previous acute
establish whether NAFLD was an independent factor CAD in course of T2D, infectious chronic diseases
of atherogenic risk beyond its association with MS and including hepatitis B and C, neoplastic and/or
haematoits components. Contextually, we tried to find out logical diseases, autoimmune and storage diseases,
whether serum levels of HSP 70 and g-GT correlated unstable medical conditions, drugs inducing HS
(sterto metabolic indices, anthropometric measures, type of oids and amiodarone) and prior use of medications
adiposity, inflammatory markers [22], and finally known to affect inflammation (aspirin), blood lipids
(staimmune status, focusing our attention on liver-spleen tins) or insulin sensibility (metformin) and finally
bariaaxis [23]. tric surgery. Alcohol abuse was ruled out, according to
the DSM-IV diagnostic criteria, by means of screening
Methods tests such as MAST (Michigan Alcohol Screening Test)
This cross-sectional study was performed enrolling out- and CAGE (Cut down, Annoyed, Guilty, and Eye
patients from September 2009 through February 2011. opener), as well as random tests for blood alcohol
conClinical investigation, blood samples and ultrasound centration and the use of a surrogate marker, e.g., Mean
(US) parameters were strictly carried out within two Corpuscular Volume.
months. Protocol was consistent with the principles of
Instrumental measurementsthe Declaration of Helsinki and participants gave their
They were performed using GE vivid systems (Generalinformed consent, according to our Medical School
Electric, Milan Italy). Transverse scanning was performedcommittee approval.Tarantino et al. Journal of Translational Medicine 2012, 10:50 Page 3 of 9
http://www.translational-medicine.com/content/10/1/50
to measure the subcutaneous adipose tissue (SAT) using was 0.09-12