The Combination of Blueberry Juice and Probiotics Ameliorate Non-Alcoholic Steatohepatitis (NASH) by Affecting SREBP-1c/PNPLA-3 Pathway via PPAR-α

Nutrients. 2017 Feb 27;9(3):198. doi: 10.3390/nu9030198.

Abstract

Nonalcoholic steatohepatitis (NASH) is liver inflammation and a major threat to public health. Several pharmaceutical agents have been used for NASH therapy but their high-rate side effects limit the use. Blueberry juice and probiotics (BP) have anti-inflammation and antibacterial properties, and may be potential candidates for NASH therapy. To understand the molecular mechanism, Sprague Dawley rats were used to create NASH models and received different treatments. Liver tissues were examined using HE (hematoxylin and eosin) and ORO (Oil Red O) stain, and serum biochemical indices were measured. The levels of peroxisome proliferators-activated receptor (PPAR)-α, sterol regulatory element binding protein-1c (SREBP-1c), Patatin-like phospholipase domain-containing protein 3 (PNPLA-3), inflammatory cytokines and apoptosis biomarkers in liver tissues were measured by qRT-PCR and Western blot. HE and ORO analysis indicated that the hepatocytes were seriously damaged with more and larger lipid droplets in NASH models while BP reduced the number and size of lipid droplets (p < 0.05). Meanwhile, BP increased the levels of SOD (superoxide dismutase), GSH (reduced glutathione) and HDL-C (high-density lipoprotein cholesterol), and reduced the levels of AST (aspartate aminotransferase), ALT (alanine aminotransferase), TG (triglycerides), LDL-C (low-density lipoprotein cholesterol) and MDA (malondialdehyde) in NASH models (p < 0.05). BP increased the level of PPAR-α (Peroxisome proliferator-activated receptor α), and reduced the levels of SREBP-1c (sterol regulatory element binding protein-1c) and PNPLA-3 (Patatin-like phospholipase domain-containing protein 3) (p < 0.05). BP reduced hepatic inflammation and apoptosis by affecting IL-6 (interleukin 6), TNF-α (Tumor necrosis factor α), caspase-3 and Bcl-2 in NASH models. Furthermore, PPAR-α inhibitor increased the level of SREBP-1c and PNPLA-3. Therefore, BP prevents NASH progression by affecting SREBP-1c/PNPLA-3 pathway via PPAR-α.

Keywords: Patatin-like phospholipase domain-containing protein 3; Peroxisome proliferator-activated receptor α; Sterol regulatory element-binding transcription factor 1c; anti-oxidant; apoptosis; biochemical indices; blueberry juices; non-alcoholic steatohepatitis; probiotics.

MeSH terms

  • Alanine Transaminase / blood
  • Animals
  • Apoptosis
  • Aspartate Aminotransferases / blood
  • Bifidobacterium animalis
  • Blueberry Plants / chemistry*
  • Caspase 3 / genetics
  • Caspase 3 / metabolism
  • Cholesterol / blood
  • Disease Models, Animal
  • Fruit / chemistry
  • Fruit and Vegetable Juices*
  • Hep G2 Cells
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Humans
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Lactobacillus delbrueckii
  • Lipid Metabolism
  • Male
  • Malondialdehyde / blood
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Non-alcoholic Fatty Liver Disease / therapy*
  • PPAR alpha / genetics
  • PPAR alpha / metabolism*
  • Phospholipases A2 / genetics
  • Phospholipases A2 / metabolism*
  • Probiotics / administration & dosage*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sterol Regulatory Element Binding Protein 1 / metabolism*
  • Streptococcus thermophilus
  • Triglycerides / blood
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Bcl2 protein, rat
  • Interleukin-6
  • Membrane Proteins
  • PPAR alpha
  • Proto-Oncogene Proteins c-bcl-2
  • Srebf1 protein, rat
  • Sterol Regulatory Element Binding Protein 1
  • Triglycerides
  • Tumor Necrosis Factor-alpha
  • Malondialdehyde
  • Cholesterol
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • PNPLA3 protein, rat
  • Phospholipases A2
  • Casp3 protein, rat
  • Caspase 3