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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2015, Vol. 9 Issue (3) : 275-287     DOI: 10.1007/s11684-015-0410-2
REVIEW |
Molecular mechanisms of fatty liver in obesity
Lixia Gan1,*(),Wei Xiang1,Bin Xie2,Liqing Yu3,*()
1. Department of Biochemistry and Molecular Biology, Third Military Medical University, Chongqing 400038, China
2. Department of Hepatobiliary Surgery, Daping Hospital & Institute of Surgery Research, Third Military Medical University, Chongqing 400042, China
3. Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, USA
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Abstract  

Nonalcoholic fatty liver disease (NAFLD) covers a spectrum of liver disorders ranging from simple steatosis to advanced pathologies, including nonalcoholic steatohepatitis and cirrhosis. NAFLD significantly contributes to morbidity and mortality in developed societies. Insulin resistance associated with central obesity is the major cause of hepatic steatosis, which is characterized by excessive accumulation of triglyceride-rich lipid droplets in the liver. Accumulating evidence supports that dysregulation of adipose lipolysis and liver de novo lipogenesis (DNL) plays a key role in driving hepatic steatosis. In this work, we reviewed the molecular mechanisms responsible for enhanced adipose lipolysis and increased hepatic DNL that lead to hepatic lipid accumulation in the context of obesity. Delineation of these mechanisms holds promise for developing novel avenues against NAFLD.

Keywords nonalcoholic fatty liver disease      insulin resistance      obesity     
Corresponding Authors: Lixia Gan,Liqing Yu   
Just Accepted Date: 22 July 2015   Online First Date: 21 August 2015    Issue Date: 26 August 2015
URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-015-0410-2     OR     http://academic.hep.com.cn/fmd/EN/Y2015/V9/I3/275
Fig.1  A schematic illustrating pathways and regulators implicated in obesity-related hepatic steatosis.
Pathways/moleculesFunctionsPatterns in NAFLDReferences
1. Hepatic uptake of nonesterified fatty acids
Caveolin-1Lipid trafficking, lipogenesisIncreased [20,21]
FATP-2, FATP-5Uptake of LCFAIncreased [15,16]
FAT/CD36Uptake of FAIncreased [17-19]
FABP1 (L-FABP), FABP-4, FABP-5Intracellular FA transportersIncreased [22,23]
2. Hepatic FA and TG synthesis
ACC-1, ACC-2Converts acetyl-CoA to malonyl-CoAIncreased [25,28]
FASSynthesizes palmitic acidIncreased [25,28]
SCD-1Synthesizes monounsaturated LCFAIncreased [25,28]
GPAT, AGPAT, DGATSynthesizes TGIncreased [52-54]
3. Hepatic fatty acid oxidation
CPT1Transfers FA to mitochondriaDecreased [71]
β-oxidation enzymesShortens LCFA into acetyl-CoAInconclusive [94,95]
4. Hepatic triglyceride secretion
Apo B-100VLDL assemblyIncreased [63]
MTPLipidation of apoB100Increased [62,63]
5. Fat lipolysis
ATGLConverts TG to DGDecreased [119]
HSLConverts DG to MGDecreased [120]
MGLConverts MG to FA and glycerolConstitutively expressed [121]
PLIN1LD-associated proteinMutated in lipodystrophy [124,136]
CIDEA,CIDECLD-associated protein that inhibits AGTLIncreased [129-131]
CGI-58ATGL activatorDecreased [65]
G0S2ATGL inhibitorIncreased [127,128]
PNPLA3TG hydrolase?SNP (I148M) predisposes this disease [67,68]
6. Regulators
PPAR-α→ CD 36, L-FABP, PGC-1α and CPT-1Decreased [74,88]
PPAR-γ→ CD 36, SREBP-1c, ChREBP, ACC, FAS, and SCD-1Increased [32,88]
LXR-α→ CD 36 and L-FABPIncreased [28,29]
PXR→ CD 36Increased [31]
SREBP-1c→ ACC-1, ACC-2, FAS, SCD-1, and DGAT1Increased [33]
ChREBP→ LPK, ACC-1, and FASIncreased [35]
FXR? LXR, SREBP-1c, and DNL→ PPAR-α, FAO, and TG clearanceDecreased [30]
PGC-1α→ Mitochondrial biogenesis and FAODecreased [74,75]
SIRT1→PPAR-α, PGC-1α, and FAO;→ FGF-21 and energy expenditure; →Lipolysis; ? SREBP-1c and DNLDecreased [72,73,75,80]
FGF-21→ FAO and energy expenditure? SREBP-1c and lipogenesisIncreased(FGF21 resistance) [83-87]
miR-122→ FAS, ACC, and SCD-1Increased [98-100]
miR-33? SREBP-1Decreased [106]
miR-34a? SIRT1Increased [107]
miR-370→ miR-122, SREBP-1c, and DNL? CPT-1 and FAOIncreased [108]
miR-613? LXR-α, SREBP-1c, ChREBP, FAS, and ACCIn vivo ? [109]
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