NASH, Fibrosis and Hepatocellular Carcinoma: Lipid Synthesis and Glutamine/Acetate Signaling

Abstract

Primary liver cancer is predicted to be the sixth most common cancer and the fourth leading cause of cancer mortality worldwide. Recent studies identified nonalcoholic fatty liver disease (NAFLD) as the underlying cause in 13–38.2% of patients with hepatocellular carcinoma unrelated to viral hepatitis and alcohol abuse. NAFLD progresses to nonalcoholic steatohepatitis (NASH), which increases the risk for the development of liver fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD is characterized by dysregulation of lipid metabolism. In addition, lipid metabolism is effected not only in NAFLD, but also in a broad range of chronic liver diseases and tumor development. Cancer cells manipulate a variety of metabolic pathways, including lipid metabolism, in order to build up their own cellular components. Identifying tumor dependencies on lipid metabolism would provide options for novel targeting strategies. This review article summarizes the research evidence on metabolic reprogramming and focuses on lipid metabolism in NAFLD, NASH, fibrosis, and cancer. As alternative routes of acetyl-CoA production for fatty acid synthesis, topics on glutamine and acetate metabolism are included. Further, studies on small compound inhibitors targeting lipid metabolism are discussed. Understanding reprogramming strategies in liver diseases, as well as the visualization of the metabolism reprogramming networks, could uncover novel therapeutic options.

A Shortcut from Metabolic-Associated Fatty Liver Disease (MAFLD) to Hepatocellular Carcinoma (HCC): c-MYC a Promising Target for Preventative Strategies and Individualized Therapy

“…Activation of lipid synthesis is very important for fast growing cells, because lipids are fundamental for functions such as membrane generation, protein modification and bioenergetics requirements. In a wide variety of tumors, de novo FA synthesis is activated independently of the levels of circulating lipids [ 25 ]. The main product of FA synthesis in the cytoplasm is saturated palmitic acid, formed by rate-limiting enzyme—SCD1—on the cytosolic side of the ER.…”

Lipid Droplet-Associated Factors, PNPLA3, TM6SF2, and HSD17B Proteins in Hepatopancreatobiliary Cancer

“…Acetyl-CoA carboxylase (ACC) subsequently catalyzes conversion into malonyl-CoA. Multi-enzyme protein fatty acid synthase (FASN) converts malonyl-CoA and acetyl CoA coupled to the acyl carrier protein (ACP) domain into a basic 16-carbon saturated FA, palmitic acid [4,6,7]. On the cytosolic side of the endoplasmic reticulum (ER), longer FAs are produced.…”

“…On the cytosoli the endoplasmic reticulum (ER), longer FAs are produced. Several types of fatty saturases such as Δ 9 -stearoyl-CoA desaturase (SCD) introduce carbon double bon is the rate-limiting enzyme catalyzing mainly the synthesis of monounsaturated 1 carbons molecules palmitoleate and oleate from palmitoyl-CoA and stearoyl-CoA tively [4,6,7]. Most cells store FAs in the form of triacylglycerols (TAGs) in the lip lets (LDs).…”

Anti‐hepatic fibrosis effects of AD‐2 affecting the Raf–MEK signaling pathway and inflammatory factors in thioacetamide‐induced liver injury

“…Liver cirrhosis has a high mortality rate (Mattiuzzi et al, 2020). Therefore, it is critical to treat hepatic fibrosis before developing into cirrhosis or even liver cancer (Kang et al, 2009;Sunami, 2020). The pathophysiology of hepatic fibrosis is closely associated with oxidative stress.…”