Background & Aims
It is well-known that hepatic triglycerides (TG) diminish with the progression of
non-alcoholic steatohepatitis (NASH), which has been designated as burned-out NASH,
but its mechanism remains unclear. We aimed to explore the changes in hepatic fatty
acid (FA) and TG metabolism with disease progression.
Methods
Hepatic expression of key genes in healthy individuals (n = 6) and patients with simple steatosis (SS, n = 10), mild NASH (fibrosis stage 1–2, n = 20), and advanced NASH (fibrosis stage 3–4, n = 20) were assessed by quantitative polymerase chain reaction.
Results
Hepatic expression of genes related to FA uptake and oxidation and very-low-density
lipoprotein synthesis/export did not differ among the groups. However, the mRNA levels
of sterol regulatory element-binding protein (SREBP)-1c and its downstream genes FA
synthase, acetyl-coenzyme A carboxylase 1, and diacylglycerol acyltransferase 1 were
inversely correlated with fibrosis stage. Immunoblot analysis revealed a remarkable
reduction in mature SREBP-1c levels in advanced NASH. Furthermore, hepatic expression
of tumor necrosis factor-α increased in accordance with fibrosis progression, which
was possibly related to the decrease in hepatic SREBP-1c expression.
Conclusions
Down-regulation of SREBP-1c and lipogenic enzymes may be associated with the development
of burned-out NASH.
Abbreviations:
ACC (acetyl-coenzyme A carboxylase), ALT (alanine aminotransferase), AMPK (adenosine monophosphate-activated protein kinase), ANGPTL4 (angiopoietin-like protein 4), AOX (acyl-coenzyme A oxidase), apo (apolipoprotein), AST (aspartate aminotransferase), BMI (body mass index), ChREBP (carbohydrate regulatory element-binding protein), CoA (coenzyme A), CPT (carnitine palmitoyl-coenzyme A transferase), CYP (cytochrome P450), DGAT (diacylglycerol acyltransferase), FA (fatty acid), FABP (fatty acid-binding protein), FAS (fatty acid synthase), FAT (fatty acid translocase), FSP (fat-specific protein), GAPDH (glyceraldehyde-3-phosphate dehydrogenase), γGT (γ-glutamyltransferase), HBV (hepatitis B virus), HCV (hepatitis C virus), HOMA-IR (homeostasis model assessment for insulin resistance), IL (interleukin), LXR (liver X receptor), MCAD (medium-chain acyl-coenzyme A dehydrogenase), MTP (microsomal triglyceride transfer protein), NAFLD (non-alcoholic fatty liver disease), NAS (NAFLD histological activity score), NASH (non-alcoholic steatohepatitis), PDK (pyruvate dehydrogenase), PGC (peroxisome proliferator-activated receptor-γ co-activator), PPAR (peroxisome proliferator-activated receptor), qPCR (quantitative polymerase chain reaction), RXR (retinoid X receptor), SCD (stearoyl-coenzyme A desaturase), SREBP (sterol regulatory element-binding protein), SS (simple steatosis), TG (triglycerides), TNF (tumor necrosis factor), TNR (TNF receptor), TP (trifunctional protein), US (ultrasonography), VLDL (very-low-density lipoprotein)Keywords
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References
- Non-alcoholic fatty liver disease: the mist gradually clears.J Hepatol. 2008; 48: S104-S112
- Clinical features and natural history of nonalcoholic steatosis syndromes.Semin Liver Dis. 2001; 21: 17-26
- Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions.Am J Gastroenterol. 1999; 94: 2467-2474
- Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity.Gastroenterology. 1999; 116: 1413-1419
- Development from simple steatosis to liver cirrhosis and hepatocellular carcinoma: a 27-year follow-up case.Clin J Gastroenterol. 2008; 1: 116-121
- Molecular mediators of hepatic steatosis and liver injury.J Clin Invest. 2004; 114: 147-152
- The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years.Hepatology. 1990; 11: 74-80
- Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease.Hepatology. 1999; 29: 664-669
- Useful parameters for distinguishing nonalcoholic steatohepatitis with mild steatosis from cryptogenic chronic hepatitis in the Japanese population.Liver Int. 2006; 26: 956-963
- Citrin deficiency as a cause of chronic liver disorder mimicking non-alcoholic fatty liver disease.J Hepatol. 2008; 49: 810-820
- Insulin resistance and hepatitis C virus: a case-control study of non-obese, non-alcoholic and non-steatotic hepatitis virus carriers with persistently normal serum aminotransferase.Liver Int. 2008; 28: 1104-1111
- Laparoscopic findings in patients with nonalcoholic steatohepatitis.Liver Int. 2006; 26: 32-38
- Design and validation of a histological scoring system for nonalcoholic fatty liver disease.Hepatology. 2005; 41: 1313-1321
- Investigation of the role of SREBP-1c in the pathogenesis of HCV-related steatosis.J Hepatol. 2008; 49: 1046-1054
- Structure of the human gene encoding sterol regulatory element binding protein-1 (SREBF1) and localization of SREBF1 and SREBF2 to chromosomes 17p11.2 and 22q13.Genomics. 1995; 25: 667-673
- Differential expression of exons 1a and 1c in mRNAs for sterol regulatory element binding protein-1 in human and mouse organs and cultured cells.J Clin Invest. 1997; 99: 838-845
- Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method.Methods. 2001; 25: 402-408
- Cytochrome P-450 hPCN3, a novel cytochrome P-450 IIIA gene product that is differentially expressed in adult human liver. CDNA and deduced amino acid sequence and distinct specificities of cDNA-expressed hPCN1 and hPCN3 for the metabolism of steroid hormones and cyclosporine.J Biol Chem. 1989; 264: 10388-10395
- Purification of human very-long-chain acyl-coenzyme A dehydrogenase and characterization of its deficiency in seven patients.J Clin Invest. 1995; 95: 2465-2473
- SREBP-1c transcription factor and lipid homeostasis: clinical perspective.Horm Res. 2007; 68: 72-82
- In vivo stabilization of nuclear retinoid X receptor α in the presence of peroxisome proliferator-activated receptor α.FEBS Lett. 2003; 543: 120-124
- Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor α (PPARα).J Biol Chem. 1998; 273: 5678-5684
- Peroxisome proliferator-activated receptor α target genes.Cell Mol Life Sci. 2004; 61: 393-416
- Comparative analysis of gene regulation by the transcription factor PPARα between mouse and human.PLoS One. 2009; 4: e6796
- Bezafibrate at clinically relevant doses decreases serum/liver triglycerides via down-regulation of sterol regulatory element-binding protein-1c in mice: a novel peroxisome proliferator-activated receptor α-independent mechanism.Mol Pharmacol. 2009; 75: 782-792
- Diverging regulation of pyruvate dehydrogenase kinase isoform gene expression in cultured human muscle cells.FEBS J. 2005; 272: 3004-3014
- Muscle-derived angiopoietin-like protein 4 is induced by fatty acids via peroxisome proliferator-activated receptor (PPAR)-δ and is of metabolic relevance in humans.Diabetes. 2009; 58: 579-589
- Adipocyte-specific gene expression and adipogenic steatosis in the mouse liver due to peroxisome proliferator-activated receptor γ1 (PPARγ1) overexpression.J Biol Chem. 2003; 278: 498-505
- Hepatic steatosis in leptin-deficient mice is promoted by the PPARγ target gene Fsp27.Cell Metab. 2008; 7: 302-311
- Tumor necrosis factor and interleukin 1 decrease RXRα, PPARα, PPARγ, LXRα, and the coactivators SRC-1, PGC-1α, and PGC-1β in liver cells.Metabolism. 2007; 56: 267-279
- Increased levels of nuclear SREBP-1c associated with fatty livers in two mouse models of diabetes mellitus.J Biol Chem. 1999; 274: 30028-30032
- Absence of sterol regulatory element-binding protein-1 (SREBP-1) ameliorates fatty livers but not obesity or insulin resistance in Lepob/Lepob mice.J Biol Chem. 2002; 277: 19353-19357
- Liver X receptor in cooperation with SREBP-1c is a major lipid synthesis regulator in nonalcoholic fatty liver disease.Hepatol Res. 2008; 38: 1122-1129
- Control of human muscle-type carnitine palmitoyltransferase I gene transcription by peroxisome proliferator-activated receptor.J Biol Chem. 1998; 273: 8560-8563
- Modulation of PPAR activity via phosphorylation.Biochim Biophys Acta. 2007; 1771: 952-960
- Hepatitis C virus core protein induces spontaneous and persistent activation of peroxisome proliferator-activated receptor α in transgenic mice: implications for HCV-associated hepatocarcinogenesis.Int J Cancer. 2008; 122: 124-131
- PPARα activation is essential for HCV core protein-induced hepatic steatosis and hepatocellular carcinoma in mice.J Clin Invest. 2008; 118: 683-694
- Polyenephosphatidylcholine prevents alcoholic liver disease in PPARα-null mice through attenuation of increases in oxidative stress.J Hepatol. 2009; 50: 1236-1246
Article info
Publication history
Published online: July 08, 2010
Accepted:
April 11,
2010
Received in revised form:
March 16,
2010
Received:
January 11,
2010
Identification
Copyright
© 2010 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
