Obesity confers an independent risk for carcinogenesis. Classically viewed as a genetic disease, owing to the discovery of tumor suppressors and oncogenes, genetic events alone are not sufficient to explain the progression and development of cancers. Tumor development is often associated with metabolic and immunological changes. In particular, obesity is found to significantly increase the mortality rate of liver cancer. As its role is not defined, a fundamental question is whether and how metabolic changes drive the development of cancer. In this review, we will dissect the current literature demonstrating that liver lipid dysfunction is a critical component driving the progression of cancer. We will discuss the involvement of inflammation in lipid dysfunction driven liver cancer development with a focus on the involvement of liver macrophages. We will first discuss the association of steatosis with liver cancer. This will be followed with a literature summary demonstrating the importance of inflammation and particularly macrophages in the progression of liver steatosis and highlighting the evidence that macrophages and macrophage produced inflammatory mediators are critical for liver cancer development. We will then discuss the specific inflammatory mediators and their roles in steatosis driven liver cancer development. Finally, we will summarize the molecular pattern (PAMP and DAMP) as well as lipid particle signals that are involved in the activation, infiltration and reprogramming of liver macrophages. We will also discuss some of the therapies that may interfere with lipid metabolism and also affect liver cancer development.
Members of estrogen-related receptors (ERRs) are orphan nuclear receptors (NRs) that play primary roles in mitochondrial biogenesis and bioenergetics. The ERRs regulate a range of cellular functions, including oxidative phosphorylation (OXPHOS) as well as glucose and lipid metabolism. ERRs are considered important targets for the treatment of metabolic diseases, particularly type II diabetes (T2D), insulin resistance (IR) and obesity. In this review, we will overview the transcriptional network regulated by the members of ERR transcriptional factors and elaborate on the regulation of ERR via its binding to PGC-1α, the primary co-activator of ERR as well as post-translational regulation of ERRs by upstream kinase signals. Recent development in ERR’s cellular function has identified lipid metabolism/lipogenesis as a process that ERR regulates, and this function significantly impacts metabolic syndrome. Here, we will focus on their roles in lipid metabolic regulation and discuss the in vivo functions of ERRs in the development of non-alcoholic fatty liver disease (NAFLD), a comorbid metabolic syndrome concurrent with T2D, IR as well as obesity. Finally, we will explore ERRs as potential therapeutic targets by discussing the ligands that serve as antagonist/agonists for ERRs as well as efforts that target DNA binding of ERR as a transcriptional factor.
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