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 |
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Authors: | Lei Hao Kyoko Ito Kuan-Hsun Huang Sudathip Sae-tan Joshua D Lambert A Catharine Ross |
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Institution: | 1. Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16802 USA;2. Department of Food Science, The Pennsylvania State University, University Park, PA 16802 USA;3. Center for Immunology and Infectious Disease, The Pennsylvania State University, University Park, PA 16802 USA |
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Abstract: | ObjectivePatatin-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.Material/methodsPNPLA3 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.ResultsIn 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.ConclusionsOur 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. |
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Keywords: | ACC1 acetyl CoA-carboxylase ALA α-linolenic acid BSA bovine serum albumin ChREBP carbohydrate response element binding protein DHA docosahexaenoic acid EPA eicosapentaenoic acid HC high-carbohydrate HF high fat LE lipid emulsion LA linoleic acid NAFLD nonalcoholic fatty liver disease OA oleic acid PNPLA3 patatin-like phospholipase domain containing 3 siRNA silencing (short-interference) RNA SREBP1c sterol regulatory element binding protein 1c TG triglyceride |
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