Abstract
Metabolic reprogramming for adaptation to the local environment has been recognized as a hallmark of cancer. Although alterations in fatty acid (FA) metabolism in cancer cells have received less attention compared to other metabolic alterations such as glucose or glutamine metabolism, recent studies have uncovered the importance of lipid metabolic reprogramming in carcinogenesis. Obesity and nonalcoholic steatohepatitis (NASH) are well-known risk factors of hepatocellular carcinoma (HCC), and individuals with these conditions exhibit an increased intake of dietary FAs accompanied by enhanced lipolysis of visceral adipose tissue due to insulin resistance, resulting in enormous exogenous FA supplies to hepatocytes via the portal vein and lymph vessels. This “lipid-rich condition” is highly characteristic of obesity- and NASH-driven HCC. Although the way in which HCC cells adapt to such a condition and exploit it to aid their progression is not understood, we recently obtained new insights into this mechanism through lipid metabolic reprogramming. In addition, accumulating evidence supports the importance of lipid metabolic reprogramming in various situations of hepatocarcinogenesis. Thus, in this review, we discuss the latest findings regarding the role of FA metabolism pathways in hepatocarcinogenesis, focusing on obesity- and NASH-driven lipid metabolic reprogramming.
Highlights
Hepatocellular carcinoma (HCC) is the second most frequent cause of cancer-related death worldwide [1]
These findings suggest that the roles of acetyl-CoA carboxylase (ACC) in HCC development may differ depending on isoforms, phosphorylation status, carcinogenesis step, and microenvironment
Antiangiogenic drugs and immune checkpoint inhibitors are currently approved as molecular targeted drugs against HCC [76], they generally provide limited therapeutic benefits for survival improvement and at present there are no drugs targeting the mutation itself or mutation-associated intracellular signaling pathways. The reasons behind this may be that HCC is a heterogeneous tumor with few driver mutations, and it often arises polyclonally based on chronic liver disease
Summary
Hepatocellular carcinoma (HCC) is the second most frequent cause of cancer-related death worldwide [1]. The most well-studied metabolic change is the Warburg effect, in which cancer cells use aerobic glycolysis instead of mitochondrial oxidative phosphorylation as building blocks for cellular proliferation, leading to increased lactate production [17]. Obese persons exhibit an increased intake of dietary FAs accompanied by enhanced lipolysis of visceral adipose tissue due to insulin resistance, resulting in enormous exogenous FA supplies to hepatocytes via the portal vein and lymph vessels. This “lipid-rich condition” is highly characteristic of obesity-driven liver cancer. In this review, we discuss the latest findings regarding the roles of FA metabolism pathways in hepatocarcinogenesis, focusing on obesityand NASH-driven lipid metabolic reprogramming
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