Editorial

DOI:10.1111/j.1478-3231.2011.02626.x

Glucagon like-peptide 1 receptor and the liver

In the wake of the global obesity epidemic, the inci-dence of non-alcoholic fatty liver disease is increasing.The condition covers the spectrum from steatosis tosteatohepatitis, fibrosis and cirrhosis. Classically, thepathogenesis is simplified to a two-hit model, involvingdevelopment of hepatic insulin resistance leading toaccumulation of triglycerides and to alteration of intra-cellular metabolism making the liver sensitive to oxida-tive stress as the first hit (2, 13). The second hit drivingthe steatosis to NASH involves overload of free radicalsarising from b-oxidation of free fatty acids in the stea-totic hepatocytes as well as effects of adipokines secretedfrom white adipose tissue (5). Although several pharma-cological agents are being evaluated, no pharmacologi-cal treatment is currently approved for the treatment ofNASH, leaving weight loss and lifestyle changes as theonly treatment in the routine clinical practice (5, 13).

Roux-en-Y gastric bypass is gaining acceptance asan effective treatment of morbidly obese patients, andis surprisingly effective in treating morbidly obese type2 diabetic patients. Improved glucose tolerance isobserved merely days after surgery and hence not cor-related to the weight loss. In addition, the procedurealso seems to reverse steatosis, steatohepatitis andfibrosis in the liver (14). As a result of the re-routingof the flow of chyme through the intestine, the secre-tion pattern of gut hormones is changed. Particularglucagon like-peptide 1 (GLP-1) and Peptide YY(PYY) are markedly elevated in response to nutrients(12). Glucagon like-peptide 1 is an incretin hormonereleased from the endocrine L-cell in the intestine inrelation to meal ingestion. Under normal conditions,the hormone stimulates insulin secretion from theb-cells and inhibits glucagon secretion from the a-cellsin a glucose-dependent manner (10). Besides effects onthe endocrine pancreas, endogenous GLP-1 has beendemonstrated to play a physiological role in the regu-lation of gastro-intestinal secretions and gastric empty-ing. The effects of GLP-1 are mediated by specificbinding of GLP-1 to the GLP-1 receptor (GLP-1r).This receptor belongs to the secretin family (type 2) ofG-protein coupled receptors, and the downstream sig-nalling is mediated (exclusively?) by an increase inintracellular cAMP. Patients suffering from type 2 dia-betes have decreased incretin effect resulting from adecreased effect of both of the incretin hormones (theother one is glucose-dependent insulinotropic poly-peptide, GIP) on the b-cell (9). However, unlike GIP,

pharmacological doses of GLP-1 are still capable ofrestoring glucose-induced insulin secretion in patientssuffering from type 2 diabetes (19). The beneficialeffects of GLP-1 have been exploited in the develop-ment the incretin or GLP-1 mimetics, a whole newtreatment strategy for type 2 diabetes, based on substi-tution with GLP-1r agonists (7). Treatment with GLP-1r agonists induces a marked weight loss in obese type2 diabetic patients (16) as well as in non-diabetic obesesubjects (1). In addition, it is evident that treatment oftype 2 diabetic patients with GLP-1r agonist improvesliver status as assessed by biochemical markers (11).

Originally, expression of GLP-1r was not mapped tothe liver (3, 11), but this classical view was recently chal-lenged by the observation in ob/ob mice (6) that60 days of treatment with GLP-1 reduced liver contentof lipids in ob/ob mice. In addition, presence of func-tional GLP-1 receptors were demonstrated usingWestern blots obtained from isolated hepatocytes, andGLP-1 receptor agonist were demonstrated to inducecAMP in primary hepatocytes. Furthermore, Guptaet al. (9) demonstrated GLP-1r in primary culture ofhuman hepatocytes. In this issue of Liver International,Svegliati-Baroni et al. present data of GLP-1r expressionin liver biopsies from patients undergoing hepatic resec-tion for focal nodular hyperplasia or hepatic adenomaand in liver biopsies from patients suffering from NASH(8). Furthermore, the expression of GLP-1r in the biop-sies from patients suffering from NASH was generallylower compared with expression in biopsies from theother patient categories. To gain enough cells to con-duct analysis of cellular events downstream of the GLP-1R activation, the authors turned to primary cultures ofhepatocytes isolated from rats with diet-induced NASH.

Treatment of the primary hepatic cell cultures withthe GLP-1r agonist exenatide induced higher expres-sion of mRNA encoding the transcription factors, per-oxisome proliferator-activated receptor alpha (Ppara)and peroxisome proliferator-activated receptor gamma(Pparg), as well as increased expression of the mRNAencoding the two key enzymes involved in both mito-chondrial and peroxisomal b-oxidation of free fattyacids (FFA): carnitine palmitoyltransferase 1A (Cpt1a)and peroxisomal acyl co-enzyme A oxidase 1 (Acox1).In hepatocytes, PPARc is generally believed to beinvolved in the regulation of synthesis of fatty acidsand storage of lipids (4). It was recently shown thatPparg is up-regulated in biopsies from patients with

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steatosis (15), and in ApoB/BAT less mice, a geneticallymodified mouse model of obesity, insulin resistanceand steatosis, exhibit increased hepatic expression ofPparg compared with wildtype mice (20). Furthermore,downregulation of the hepatic Pparg expressionreverses the steatotic phenotype in this mouse model(20). However, another study applying a gene rescueapproach to PPARc deficient mice showed that rescueof Pparg expression in both liver and adipose tissuereversed the steatohepatitis induced by methionine andcholine deficient diet (18), indicating that PPARcshould be activated in both adipocytes as well as he-patocytes to reverse steatosis. Though stimulation ofhepatocytes in primary culture with exenatide results inupregulation of Pparg, it is unclear whether this resultsin storage of lipids and synthesis of fatty acids, becausethe stimulation also upregulates adenosine monophos-phate kinase (Ampk). PPARa and Ampk are involvedin regulation of oxidation of free fatty acids (4, 17). Onthe basis of these observations, one could speculatewhether GLP-1 actually induces a futile circle burningfat in the liver. The observations of up-regulation ofenzymes involved in the oxidation of lipid also raiseconcerns whether GLP-1 treatment, actually, as a con-sequence of increased oxidation of FFA, might induceincreased oxidative stress in the hepatocytes. Thisimportant question was not addressed by the authors,but in ob/ob mice, Ding et al. (6) showed that GLP-1actually deceased markers of oxidative stress in the he-patocytes.

The classical view that the liver is not directly influ-enced by GLP-1 is challenged by the work from Svegli-ati-Baroni et al. presented in this issue. The authorspresent data showing expression of GLP-1R in liverbiopsies from humans, and show that GLP-1 regulatesexpression of transcription factors and enzymesinvolved in the hepatic metabolism of lipids usinghepatocytes isolated from rats with diet-induced NASH.Together with recent observation also showing expres-sion of GLP-1R in the liver of mice and humans, theclassical view might need to be revised, as it appears thatat least a subset of hepatocytes expresses GLP-1R andare directly stimulated by GLP-1.

On the basis of the know physiological effects ofGLP-1 in type 2 diabetic patients, it is possible thatpatients suffering from type 2 diabetes and NASH mightbenefit from treatment with incretin mimetics. The datapresented by Svegliati-Baroni et al. indicate that incre-tin mimetics also could be helpful in the small group ofpatients only suffering from NASH, but this interestingquestion needs more attention in future studies.

Jens Pedersen and Jens Juul HolstDepartment of Biomedical Sciences, The Panum Institute,

University of Copenhagen, DK-2200, Copenhagen N,Denmark

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Editorial Pedersen and Holst

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