Immunometabolic factors contributing to obesity-linked hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a major public health concern that is promoted by obesity and associated liver complications. Onset and progression of HCC in obesity is a multifactorial process involving complex interactions between the metabolic and immune system, in which chronic liver damage resulting from metabolic and inflammatory insults trigger carcinogenesis-promoting gene mutations and tumor metabolism. Moreover, cell growth and proliferation of the cancerous cell, after initiation, requires interactions between various immunological and metabolic pathways that provide stress defense of the cancer cell as well as strategic cell death escape mechanisms. The heterogenic nature of HCC in addition to the various metabolic risk factors underlying HCC development have led researchers to focus on examining metabolic pathways that may contribute to HCC development. In obesity-linked HCC, oncogene-induced modifications and metabolic pathways have been identified to support anabolic demands of the growing HCC cells and combat the concomitant cell stress, coinciding with altered utilization of signaling pathways and metabolic fuels involved in glucose metabolism, macromolecule synthesis, stress defense, and redox homeostasis. In this review, we discuss metabolic insults that can underlie the transition from steatosis to steatohepatitis and from steatohepatitis to HCC as well as aberrantly regulated immunometabolic pathways that enable cancer cells to survive and proliferate in the tumor microenvironment. We also discuss therapeutic modalities targeted at HCC prevention and regression. A full understanding of HCC-associated immunometabolic changes in obesity may contribute to clinical treatments that effectively target cancer metabolism.

Sterol O-acyltransferase (SOAT/ACAT) activity is required to form cholesterol crystals in hepatocyte lipid droplets

“…Metabolic dysfunction-associated steatohepatitis (MASH) has become a global health concern [32, 33], but there is incomplete understanding of its pathogenesis and treatment. Hepatocyte cholesterol crystals are associated with MASH, but not simple steatosis, in humans and in rodent disease models that are induced by cholesterol enriched diet [3, 4]. These crystals may induce liver inflammation similarly to how they induce inflammation in atherosclerotic plaques [3, 17, 24, 29].…”

“…However, excess unesterified (free) cholesterol can exert damaging and stressful effects on cellular processes that promote disease [2]. One disease linked to excess free cholesterol is metabolic dysfunction-associated steatohepatitis (MASH), also known as non-alcoholic steatohepatitis [3,4]. Free cholesterol in liver is elevated in people with MASH compared to simple steatosis [5][6][7] and rodent studies show hepatic cholesterol accumulation triggers the progression of steatosis to MASH [4,[8][9][10][11][12][13][14].…”

“…One disease linked to excess free cholesterol is metabolic dysfunction-associated steatohepatitis (MASH), also known as non-alcoholic steatohepatitis [3,4]. Free cholesterol in liver is elevated in people with MASH compared to simple steatosis [5][6][7] and rodent studies show hepatic cholesterol accumulation triggers the progression of steatosis to MASH [4,[8][9][10][11][12][13][14]. Deciphering the link between hepatic cholesterol excess and MASH may provide insight regarding its pathogenesis and reveal a strategy for uncoupling this link to improve liver health outcomes for at risk patients.…”

Protective Effects of Hepatocyte Stress Defenders, Nrf1 and Nrf2, Against MASLD Progression

“…The most common case is asymptomatic simple steatosis whereas ~20% of people with MASLD progress to metabolic dysfunction associated steatohepatitis (MASH), characterized by liver steatosis, inflammation, and fibrosis. People with MASH have higher risk for cirrhosis and hepatocellular carcinoma (HCC), and so treatments that delay or reverse MASH onset and its progression to more severe disease stages are in need (4)(5)(6)(7)(8). A major factor driving MASH is the accumulation of hepatotoxic lipids that impose stress by causing reactive oxygen species (ROS) production, organelle damage and dysfunction, and inflammatory signaling which in turn promote fibrosis via activating stellate cells (4,(8)(9)(10)(11).…”

“…People with MASH have higher risk for cirrhosis and hepatocellular carcinoma (HCC), and so treatments that delay or reverse MASH onset and its progression to more severe disease stages are in need (4)(5)(6)(7)(8). A major factor driving MASH is the accumulation of hepatotoxic lipids that impose stress by causing reactive oxygen species (ROS) production, organelle damage and dysfunction, and inflammatory signaling which in turn promote fibrosis via activating stellate cells (4,(8)(9)(10)(11). As this is a pivotal point for adverse effects and risk factor for mortality and severe comorbidities (5,12), alleviating or resolving lipid-induced stress in the liver may be critical to improve outcomes for patients with MASH.…”