title: Shifts in dietary carbohydrate-lipid exposure regulate expression of the non-alcoholic fatty liver disease-associated gene PNPLA3/adiponutrin in mouse liver and HepG2 human liver cells.
abstract: OBJECTIVE
  Patatin-like phospholipase domain containing 3 (PNPLA3, adiponutrin) has been identified as a modifier of lipid metabolism. To better understand the physiological role of PNPLA3/adiponutrin, we have investigated its regulation in intact mice and human hepatocytes under various nutritional/metabolic conditions.
  
  
  METHODS
  PNPLA3 gene expression was determined by real-time PCR in liver of C57BL/6 mice after dietary treatments and in HepG2 cells exposed to various nutritional/metabolic stimuli. Intracellular lipid content was determined in HepG2 cells after siRNA-mediated knockdown of PNPLA3.
  
  
  RESULTS
  In vivo, mice fed a high-carbohydrate (HC) liquid diet had elevated hepatic lipid content, and PNPLA3 mRNA and protein expression, compared to chow-fed mice. Elevated expression was completely abrogated by addition of unsaturated lipid emulsion to the HC diet. By contrast, in mice with high-fat diet-induced steatosis, Pnpla3 expression did not differ compared to low-fat fed mice. In HepG2 cells, Pnpla3 expression was reversibly suppressed by glucose depletion and increased by glucose refeeding, but unchanged by addition of insulin and glucagon. Several unsaturated fatty acids each significantly decreased Pnpla3 mRNA, similar to lipid emulsion in vivo. However, Pnpla3 knockdown in HepG2 cells did not alter total lipid content in high glucose- or oleic acid-treated cells.
  
  
  CONCLUSIONS
  Our results provide evidence that PNPLA3 expression is an early signal/signature of carbohydrate-induced lipogenesis, but its expression is not associated with steatosis per se. Under lipogenic conditions due to high-carbohydrate feeding, certain unsaturated fatty acids can effectively suppress both lipogenesis and PNPLA3 expression, both in vivo and in a hepatocyte cell line.
authors: Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16802 USA.
authors: Lei
authors: L
authors: Hao
authors: Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16802 USA.
authors: Kyoko
authors: K
authors: Ito
authors: Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16802 USA.
authors: Kuan-Hsun
authors: KH
authors: Huang
authors: Department of Food Science, The Pennsylvania State University, University Park, PA 16802 USA.
authors: Sudathip
authors: S
authors: Sae-tan
authors: Department of Food Science, The Pennsylvania State University, University Park, PA 16802 USA.
authors: Joshua D
authors: JD
authors: Lambert
authors: Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16802 USA; Center for Immunology and Infectious Disease, The Pennsylvania State University, University Park, PA 16802 USA. Electronic address: acr6@psu.edu.
authors: A Catharine
authors: AC
authors: Ross
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D059305:Diet, High-Fat / Q000379:methods; D004040:Dietary Carbohydrates / Q000378:metabolism*; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics*; D005934:Glucagon / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics*; D008055:Lipids / Q000235:genetics*; D050155:Lipogenesis / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease
chemical_list: D004040:Dietary Carbohydrates; D007328:Insulin; D008055:Lipids; D008565:Membrane Proteins; C436316:adiponutrin; D005934:Glucagon; D005947:Glucose
keywords: Glucose; Lipid emulsion; Nonalcoholic fatty liver disease; Patatin-like phospholipase domain containing 3