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      Non-Alcoholic Fatty Liver Disease (NAFLD) and Its Connection with Insulin Resistance, Dyslipidemia, Atherosclerosis and Coronary Heart Disease

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          Abstract

          Non-alcoholic fatty liver disease is marked by hepatic fat accumulation not due to alcohol abuse. Several studies have demonstrated that NAFLD is associated with insulin resistance leading to a resistance in the antilipolytic effect of insulin in the adipose tissue with an increase of free fatty acids (FFAs). The increase of FFAs induces mitochondrial dysfunction and development of lipotoxicity. Moreover, in subjects with NAFLD, ectopic fat also accumulates as cardiac and pancreatic fat. In this review we analyzed the mechanisms that relate NAFLD with metabolic syndrome and dyslipidemia and its association with the development and progression of cardiovascular disease.

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          Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance.

          Durba Pal, Suman Dasgupta, Rakesh Kundu … (2012)
          Toll-like receptor 4 (TLR4) has a key role in innate immunity by activating an inflammatory signaling pathway. Free fatty acids (FFAs) stimulate adipose tissue inflammation through the TLR4 pathway, resulting in insulin resistance. However, current evidence suggests that FFAs do not directly bind to TLR4, but an endogenous ligand for TLR4 remains to be identified. Here we show that fetuin-A (FetA) could be this endogenous ligand and that it has a crucial role in regulating insulin sensitivity via Tlr4 signaling in mice. FetA (officially known as Ahsg) knockdown in mice with insulin resistance caused by a high-fat diet (HFD) resulted in downregulation of Tlr4-mediated inflammatory signaling in adipose tissue, whereas selective administration of FetA induced inflammatory signaling and insulin resistance. FFA-induced proinflammatory cytokine expression in adipocytes occurred only in the presence of both FetA and Tlr4; removing either of them prevented FFA-induced insulin resistance. We further found that FetA, through its terminal galactoside moiety, directly binds the residues of Leu100-Gly123 and Thr493-Thr516 in Tlr4. FFAs did not produce insulin resistance in adipocytes with mutated Tlr4 or galactoside-cleaved FetA. Taken together, our results suggest that FetA fulfills the requirement of an endogenous ligand for TLR4 through which lipids induce insulin resistance. This may position FetA as a new therapeutic target for managing insulin resistance and type 2 diabetes.
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            Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms.

            E Bugianesi, A Gastaldelli, E Vanni … (2005)
            Non-alcoholic fatty liver disease (NAFLD) has been associated with the metabolic syndrome. However, it is not clear whether insulin resistance is an independent feature of NAFLD, and it remains to be determined which of the in vivo actions of insulin are impaired in this condition. We performed a two-step (1.5 and 6 pmol min(-1) kg(-1)) euglycaemic insulin clamp coupled with tracer infusion ([6,6-2H2]glucose and [2H5]glycerol) and indirect calorimetry in 12 non-obese, normolipidaemic, normotensive, non-diabetic patients with biopsy-proven NAFLD and six control subjects. In NAFLD patients, endogenous glucose production (basal and during the clamp) was normal; however, peripheral glucose disposal was markedly decreased (by 30% and 45% at the low and high insulin doses, respectively, p<0.0001) at higher plasma insulin levels (p=0.05), due to impaired glucose oxidation (p=0.003) and glycogen synthesis (p<0.001). Compared with control subjects, glycerol appearance and lipid oxidation were significantly increased in NAFLD patients in the basal state, and were suppressed by insulin to a lesser extent (p<0.05-0.001). The lag phase of the in vitro copper-catalysed peroxidation of LDL particles was significantly shorter in the patients than in the control subjects (48+/-12 vs 63+/-13 min, p<0.04). Lipid oxidation was significantly related to endogenous glucose production, glucose disposal, the degree of hepatic steatosis, and LDL oxidisability. Insulin resistance appears to be an intrinsic defect in NAFLD, with the metabolic pattern observed indicating that adipose tissue is an important site.
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              Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease.

              Faidon Magkos, Ehab B Mohammed-Elhassan, Richard W. Patterson … (2008)
              Steatosis in patients with nonalcoholic fatty liver disease (NAFLD) is due to an imbalance between intrahepatic triglyceride (IHTG) production and export. The purpose of this study was to evaluate TG metabolism in adipose tissue and liver in NAFLD. Fatty acid, VLDL-TG, and VLDL-apolipoprotein B-100 (apoB100) kinetics were assessed by using stable isotope tracers in 14 nondiabetic obese subjects with NAFLD (IHTG, 22.7% +/- 2.0%) and 14 nondiabetic obese subjects with normal IHTG content (IHTG, 3.4% +/- 0.4%), matched on age, sex, body mass index, and percent body fat. Compared with the normal IHTG group, the NAFLD group had greater rates of palmitate release from adipose tissue into plasma (85.4 +/- 6.6 and 114.1 +/- 8.1 micromol/min, respectively; P = .01) and VLDL-TG secretion (11.4 +/- 1.1 and 24.3 +/- 3.1 micromol/min, respectively; P = .001); VLDL-apoB100 secretion rates were not different between groups. The increase in VLDL-TG secretion was primarily due to an increased contribution from "nonsystemic" fatty acids, presumably derived from lipolysis of intrahepatic and intra-abdominal fat and de novo lipogenesis. VLDL-TG secretion rate increased linearly with increasing IHTG content in subjects with normal IHTG but reached a plateau when IHTG content was >/=10% (r = 0.618, P < .001). Obese persons with NAFLD have marked alterations in both adipose tissue (increased lipolytic rates) and hepatic (increased VLDL-TG secretion) TG metabolism. Fatty acids derived from nonsystemic sources are responsible for the increase in VLDL-TG secretion. However, the increase in hepatic TG export is not adequate to normalize IHTG content.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Nutrients
                Journal ID (iso-abbrev): Nutrients
                Journal ID (publisher-id): nutrients
                Title: Nutrients
                Publisher: MDPI
                ISSN (Electronic): 2072-6643
                Publication date (Electronic): 10 May 2013
                Publication date Collection: May 2013
                Volume: 5
                Issue: 5
                Pages: 1544-1560
                Affiliations
                [1 ]Institute of Clinical Physiology National Research Council, Pisa 56100, Italy; E-Mails: m.gaggini@ 123456ifc.cnr.it (M.G.); mariangela_morelli@ 123456yahoo.it (M.M.); emma.buzzigoli@ 123456ifc.cnr.it (E.B.)
                [2 ]Division of Diabetes, University of Texas Health Science Center, San Antonio, TX 78229, USA; E-Mail: albarado@ 123456iuthscsa.edu
                [3 ]Department of Medical Sciences, Division of Gastro-Hepatology, San Giovanni Battista Hospital, University of Turin, Turin 10126, Italy; E-Mail: elisabetta.bugianesi@ 123456unito.it
                Author notes
                [* ] Author to whom correspondence should be addressed; E-Mail: amalia@ 123456ifc.cnr.it ; Tel.: +39-050-315-2680/79; Fax: +39-050-315-2166.
                Article
                Publisher ID: nutrients-05-01544
                DOI: 10.3390/nu5051544
                PMC ID: 3708335
                PubMed ID: 23666091
                SO-VID: 6599d0ac-f296-44b5-9696-db170efcd38c
                Copyright © © 2013 by the authors; licensee MDPI, Basel, Switzerland.
                License:

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                Date received : 25 February 2013
                Date revision received : 12 April 2013
                Date accepted : 16 April 2013
                Categories
                Subject: Review

                ScienceOpen disciplines: Nutrition & Dietetics
                Keywords: non-alcoholic fatty liver(nafld),steatosis,visceral fat,lipotoxicity,insulin resistance,free fatty acids,dyslipidemia,cardiometabolic risk
                Data availability:
                ScienceOpen disciplines: Nutrition & Dietetics
                Keywords: non-alcoholic fatty liver(nafld), steatosis, visceral fat, lipotoxicity, insulin resistance, free fatty acids, dyslipidemia, cardiometabolic risk

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