Human fatty liver disease: old questions and new insights - PubMed (original) (raw)
Review
Human fatty liver disease: old questions and new insights
Jonathan C Cohen et al. Science. 2011.
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem that affects one-third of adults and an increasing number of children in developed countries. The disease begins with the aberrant accumulation of triglyceride in the liver, which in some individuals elicits an inflammatory response that can progress to cirrhosis and liver cancer. Although NAFLD is strongly associated with obesity and insulin resistance, its pathogenesis remains poorly understood, and therapeutic options are limited. Here, we discuss recent mechanistic insights into NAFLD, focusing primarily on those that have emerged from human genetic and metabolic studies.
Figures
Fig. 1
The disease spectrum of nonalcoholic fatty liver disease. (A) Schematic of progression of NAFLD. The accumulation of TG within lipid droplets in hepatocytes causes steatosis. Steatosis associated with inflammation, cell death, and fibrosis is referred to as NASH, which can progress to cirrhosis. Individuals with cirrhosis have an increased risk of hepatocellular carcinoma. (B) Histological sections illustrating normal liver, steatosis, NASH, and cirrhosis. Collagen fibers are stained blue with Masson’s trichrome stain. The portal triad (PT), which consists of the hepatic artery, portal vein, and bile duct, and the central vein (CV) are shown.
Fig. 2
Metabolism of TG in the liver. The three major sources of FFAs are diet, endogenous synthesis, and peripheral tissues. FFAs have four possible fates. They can be metabolized by β oxidation (β-OX) in mitochondria, esterified and stored as TG in lipid droplets, used to form other lipids (not shown), or packaged with apoB into VLDL and secreted into blood. Processes that increase FFA and TG input or reduce FFA and TG output cause hepatic steatosis. Carbohydrate intake increases glucose and insulin levels, which activate two transcription factors in the liver that promote de novo lipogenesis: ChREBP and SREBP-1c. Insulin inhibits lipolysis in adipose tissue by suppressing ATGL. Chylo, chylomicron; TCA, tricarboxylic acid.
Similar articles
- The American lifestyle-induced obesity syndrome diet in male and female rodents recapitulates the clinical and transcriptomic features of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.
Harris SE, Poolman TM, Arvaniti A, Cox RD, Gathercole LL, Tomlinson JW. Harris SE, et al. Am J Physiol Gastrointest Liver Physiol. 2020 Sep 1;319(3):G345-G360. doi: 10.1152/ajpgi.00055.2020. Epub 2020 Aug 5. Am J Physiol Gastrointest Liver Physiol. 2020. PMID: 32755310 Free PMC article. - Genetic Factors in the Pathogenesis of Nonalcoholic Fatty Liver and Steatohepatitis.
Dongiovanni P, Romeo S, Valenti L. Dongiovanni P, et al. Biomed Res Int. 2015;2015:460190. doi: 10.1155/2015/460190. Epub 2015 Jul 27. Biomed Res Int. 2015. PMID: 26273621 Free PMC article. Review. - Fructose as a key player in the development of fatty liver disease.
Basaranoglu M, Basaranoglu G, Sabuncu T, Sentürk H. Basaranoglu M, et al. World J Gastroenterol. 2013 Feb 28;19(8):1166-72. doi: 10.3748/wjg.v19.i8.1166. World J Gastroenterol. 2013. PMID: 23482247 Free PMC article. Review. - Nrf2 deletion causes "benign" simple steatosis to develop into nonalcoholic steatohepatitis in mice fed a high-fat diet.
Wang C, Cui Y, Li C, Zhang Y, Xu S, Li X, Li H, Zhang X. Wang C, et al. Lipids Health Dis. 2013 Nov 4;12:165. doi: 10.1186/1476-511X-12-165. Lipids Health Dis. 2013. PMID: 24188280 Free PMC article. - Translational approaches: from fatty liver to non-alcoholic steatohepatitis.
Rosso N, Chavez-Tapia NC, Tiribelli C, Bellentani S. Rosso N, et al. World J Gastroenterol. 2014 Jul 21;20(27):9038-49. doi: 10.3748/wjg.v20.i27.9038. World J Gastroenterol. 2014. PMID: 25083077 Free PMC article. Review.
Cited by
- Advanced Liver-on-a-Chip Model for Evaluating Drug Metabolism and Hepatotoxicity.
Frojdenfal S, Zuchowska A. Frojdenfal S, et al. Biosensors (Basel). 2024 Sep 6;14(9):435. doi: 10.3390/bios14090435. Biosensors (Basel). 2024. PMID: 39329810 Free PMC article. - 8-Prenylgenistein Isoflavone in Cheonggukjang Acts as a Novel AMPK Activator Attenuating Hepatic Steatosis by Enhancing the SIRT1-Mediated Pathway.
Arulkumar R, Jung HJ, Noh SG, Kim HW, Chung HY. Arulkumar R, et al. Int J Mol Sci. 2024 Sep 8;25(17):9730. doi: 10.3390/ijms25179730. Int J Mol Sci. 2024. PMID: 39273677 Free PMC article. - Strategy for treating MAFLD: Electroacupuncture alleviates hepatic steatosis and fibrosis by enhancing AMPK mediated glycolipid metabolism and autophagy in T2DM rats.
Duan H, Song S, Li R, Hu S, Zhuang S, Liu S, Li X, Gao W. Duan H, et al. Diabetol Metab Syndr. 2024 Sep 11;16(1):218. doi: 10.1186/s13098-024-01432-7. Diabetol Metab Syndr. 2024. PMID: 39261952 Free PMC article. - Causal relationships between neuropsychiatric disorders and nonalcoholic fatty liver disease: A bidirectional Mendelian randomization study.
Wang S, Gao H, Lin P, Qian T, Xu L. Wang S, et al. BMC Gastroenterol. 2024 Sep 4;24(1):299. doi: 10.1186/s12876-024-03386-6. BMC Gastroenterol. 2024. PMID: 39227758 Free PMC article. - Exosome prospects in the diagnosis and treatment of non-alcoholic fatty liver disease.
Tamimi A, Javid M, Sedighi-Pirsaraei N, Mirdamadi A. Tamimi A, et al. Front Med (Lausanne). 2024 Jul 31;11:1420281. doi: 10.3389/fmed.2024.1420281. eCollection 2024. Front Med (Lausanne). 2024. PMID: 39144666 Free PMC article. Review.
References
- Szczepaniak LS, et al. Am. J. Physiol. Endocrinol. Metab. 2005;288:462. - PubMed
- Argo CK, Caldwell SH. Clin. Liver Dis. 2009;13:511. - PubMed
- Starley BQ, Calcagno CJ, Harrison SA. Hepatology. 2010;51:1820. - PubMed
- Hebbard L, George J. Nat. Rev. Gastroenterol. Hepatol. 2011;8:35. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
- P01 HL020948/HL/NHLBI NIH HHS/United States
- RL1HL092550/HL/NHLBI NIH HHS/United States
- RL1 HL092550-05/HL/NHLBI NIH HHS/United States
- RL1 HL092550/HL/NHLBI NIH HHS/United States
- UL1DE109584/DE/NIDCR NIH HHS/United States
- UL1 DE019584/DE/NIDCR NIH HHS/United States
- UL1 DE019584-05/DE/NIDCR NIH HHS/United States
- P01 HL020948-35/HL/NHLBI NIH HHS/United States
- P01 HL20948/HL/NHLBI NIH HHS/United States
- R01 DK090066/DK/NIDDK NIH HHS/United States
LinkOut - more resources
Full Text Sources
Other Literature Sources