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Abstract
Nonalcoholic fatty liver disease (NAFLD) refers to the pathologic buildup of extra fat in the form of triglycerides in liver cells without excessive alcohol intake. NAFLD became the most common cause of chronic liver disease that is tightly associated with key aspects of metabolic disorders, including insulin resistance, obesity, diabetes, and metabolic syndrome. It is generally accepted that multiple mechanisms and pathways are involved in the pathogenesis of NAFLD. Heredity, sedentary lifestyle, westernized high sugar saturated fat diet, metabolic derangements, and gut microbiota, all may interact on a on genetically susceptible individual to cause the disease initiation and progression. While there is an unquestionable role for gene-diet interaction in the etiopathogenesis of NAFLD, it is increasingly apparent that epigenetic processes can orchestrate many aspects of this interaction and provide additional mechanistic insight. Exciting research demonstrated that epigenetic alterations in chromatin can influence gene expression chiefly at the transcriptional level in response to unbalanced diet, and therefore predispose an individual to NAFLD. Thus, further discoveries into molecular epigenetic mechanisms underlying the link between nutrition and aberrant hepatic gene expression can yield new insights into the pathogenesis of NAFLD, and allow innovative epigenetic-based strategies for its early prevention and targeted therapies. Herein, we outline the current knowledge of the interactive role of a high-fat high-calories diet and gene expression through DNA methylation and histone modifications on the pathogenesis of NAFLD. We also provide perspectives on the advancement of the epigenomics in the field and possible shortcomings and limitations ahead.
Highlights
Nonalcoholic fatty liver disease (NAFLD) includes a spectrum of features spanning from the simple accumulation of triglycerides (TG) in hepatocytes to nonalcoholic steatohepatitis (NASH), which is characterized by the presence of an inflammatory infiltrate and hepatocellular injury [1], and may further evolve to cirrhosis and hepatocellular carcinoma (HCC) [2]
Emerging evidence suggests that there is a relationship between different noncoding RNAs (ncRNAs) and their roles in the regulation of gene networks involved in the development of metabolic diseases including obesity and NAFLD [18,42,43,44,45]
This group of researchers has shown that hepatic lipid accumulation is linked with aberrant histone H3K4 and H3K9 trimethylation in PPARα and increased expression of genes involved in lipid metabolism in high-fat western type diet (HFD)-fed mice [114]
Summary
Nonalcoholic fatty liver disease (NAFLD) includes a spectrum of features spanning from the simple accumulation of triglycerides (TG) in hepatocytes (hepatic steatosis) to nonalcoholic steatohepatitis (NASH), which is characterized by the presence of an inflammatory infiltrate and hepatocellular injury [1], and may further evolve to cirrhosis and hepatocellular carcinoma (HCC) [2]. Genetic and environmental factors were thought to be independently associated with metabolic disorders, huge evidence confirms the existence of complex interactions between genetic background and environmental influences, diet, to modulate individual risk of NAFLD development and its severity and progression [33] This is not surprising, since nutritional genomic studies revealed that nutrition is most likely the key environmental factor that exerts its impact on health outcomes by directly affecting the expression of key genes involved in major metabolic pathways. The effect of HFD on genes involved in hepatic fat accumulation and steatosis was shown to be mediated by epigenetic factors, which play crucial roles in the molecular initiation of liver dysfunction and NAFLD development [37,38] Despite these encouraging data, we still do not have a firm handle on how and when epigenetic marks that occur in response to an HFD alter gene expression in NAFLD. Understanding this potential interaction and the resulting pathological signals may lead to identification of epigenetic marks that predispose an individual to NAFLD, and subsequently, could allow early preventive and therapeutic strategies for those at a high risk for the disease
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