Abstract
Long-term adherence to a high-fat, high-calorie diet influences human health and causes obesity, metabolic syndrome and nonalcoholic steatohepatitis (NASH). Inflammation plays a key role in the development of NASH; however, the mechanism of inflammation induced by over-nutrition remains largely unknown. In this study, we fed Bama minipigs a high-fat, high-sucrose diet (HFHSD) for 23 months. The pigs exhibited characteristics of metabolic syndrome and developed steatohepatitis with greatly increased numbers of inflammatory cells, such as lymphocytes (2.27-fold, P<0.05), Kupffer cells (2.59-fold, P<0.05), eosinophils (1.42-fold, P<0.05) and neutrophils (2.77-fold, P<0.05). High-throughput RNA sequencing (RNA-seq) was performed to explore the systemic transcriptome of the pig liver during inflammation. Approximately 18.2 gigabases of raw sequence data were generated, and over 303 million high-quality reads were assembled into 21,126 unigenes. RNA-seq data analysis showed that 822 genes were differentially expressed in liver (P<0.05) between the HFHSD and control groups. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the process of inflammation involved the inflammatory signal transduction-related toll-like receptor, MAPK, and PPAR signaling pathways; the cytokine-related chemokine signaling, cytokine-cytokine receptor interaction, and IL2, IL4, IL6, and IL12 signaling pathways; the leukocyte receptor signaling-related T cell, B cell, and natural killer cell signaling pathways; inflammatory cell migration and invasion- related pathways; and other pathways. Moreover, we identified several differentially expressed inflammation-related genes between the two groups, including FOS, JUN, TLR7, MYC, PIK3CD, VAV3, IL2RB and IL4R, that could be potential targets for further investigation. Our study suggested that long-term HFHSD induced obesity and liver inflammation, providing basic insight into the molecular mechanism of this condition and laying the groundwork for further studies on obesity and steatohepatitis.
Highlights
Obesity, metabolic syndrome and the associated chronic inflammation are among the most prevalent diseases that impose enormous health and economic burdens on governments around the world and on the global economy [1]
We focused on the genes and mechanisms involved in the response of swine livers to inflammation induced by HFHSD using RNA sequencing analysis (RNA-Seq)
The level of blood glucose in the HFHSD pigs did not show a significant difference from controls, their insulin had remarkably increased by 4.96-fold (28.32 vs. 5.71, P,0.001), signifying hyperinsulinemia
Summary
Metabolic syndrome and the associated chronic inflammation are among the most prevalent diseases that impose enormous health and economic burdens on governments around the world and on the global economy [1]. Nonalcoholic steatohepatitis (NASH), a key stage of NAFLD, is characterized by hepatic steatosis, inflammation and fibrosis and is emerging as one of the most common liver diseases and a leading cause of cirrhosis [3]. Inflammation is believed to be the driving force behind the development of NASH and acts as a critical predictor of the histological progression to fibrosis and cirrhosis; inflammation represents a potentially major therapeutic target in NASH [4]. The potential mechanisms of inflammation in NASH include systemic lipotoxicity as a result of over-nutrition, oxidative stress and the production of proinflammatory cytokines, which activate the immune response and drive inflammation [5,6]. Proinflammatory cytokines such as IL-6 and TNFa act to trigger the diverse hepatic lesions of NASH by inducing hepatic inflammation and fibrosis, which eventually lead to end-stage liver diseases [7].
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