Fat Induces Glucose Metabolism in Nontransformed Liver Cells and Promotes Liver Tumorigenesis

Abstract

Hepatic fat accumulation is associated with diabetes and hepatocellular carcinoma (HCC). Here we characterize the metabolic response that high fat availability elicits in livers prior to disease development. After a short term on a high fat diet, otherwise healthy mice showed elevated hepatic glucose uptake and increased glucose contribution to serine and pyruvate carboxylase activity compared to control diet mice. This glucose phenotype occurred independently from transcriptional or proteomic programming, which identifies increased peroxisomal and lipid metabolism pathways. High fat diet-fed mice exhibited increased lactate production when challenged with glucose. Consistently, administration of an oral glucose bolus to healthy individuals revealed a correlation between waist circumference and lactate secretion in a human cohort. In vitro, palmitate exposure stimulated production of reactive oxygen species and subsequent glucose uptake and lactate secretion in hepatocytes and liver cancer cells.Furthermore, high fat diet enhanced the formation of HCC compared to control diet in mice exposed to a hepatic carcinogen. Regardless of the dietary background, all murine tumors showed similar alterations in glucose metabolism to those identified in fat exposed non-transformed mouse livers; however, particular lipid species were elevated in high fat diet tumor and nontumor-bearing high fat diet liver tissue. These findings suggest that fat can induce glucosemediated metabolic changes in non-transformed liver cells similar to those found in HCC.Significance: With obesity-induced hepatocellular carcinoma on a rising trend, this study shows in normal, non-transformed livers that fat induces glucose metabolism similar to an oncogenic transformation.

Oxidative stress in obesity-associated hepatocellular carcinoma: sources, signaling and therapeutic challenges

“…It has been shown that high-fat content in the diet can alter glucose metabolism in normal liver cells to a Warburg-like phenotype, suggesting that excessive fat availability can metabolically prime normal hepatocytes for neoplastic transformation. The hyperactivation of glucose metabolism induced by high-fat availability is mediated by increased peroxisomal ROS production [36], highlighting the close link between energy metabolism and modifications in the oxidative status of the cells. In this sense, the availability of different nutrients and metabolites can influence not only the activity and the expression of anti-and prooxidant enzymes, but also feed metabolic pathways that burst ROS generation, driving metabolic reprograming, and carcinogenesis.…”

Cancer metabolism and dietary interventions

“…HFDs profoundly potentiates malignant progress in pancreatic, liver, prostate, colon, and breast cancers [110][111][112][113][114] . Moreover, HFDs synergistically induce the malignant transformation of liver cells or elicit tumorigenesis by nourishing stem cells or suppressing the tumor immune microenvironment [115][116][117] .…”

Hepatocellular Carcinoma and Obesity, Type 2 Diabetes Mellitus, Cardiovascular Disease: Causing Factors, Molecular Links, and Treatment Options

“…Obesity can modulate glucose metabolism to promote HCC progression. Saturated fatty acids such as palmitate impact cancer stem cell properties, production of reactive oxidative species, and glucose metabolism to enhance HCC initiation and progression ( 24 , 25 ). In addition, feeding a HFD promoted the production of lactate when the mice received glucose ( 25 ).…”

“…Saturated fatty acids such as palmitate impact cancer stem cell properties, production of reactive oxidative species, and glucose metabolism to enhance HCC initiation and progression ( 24 , 25 ). In addition, feeding a HFD promoted the production of lactate when the mice received glucose ( 25 ). T-regulatory cells (Tregs) can proliferate in lactate-rich environments, which mediates suppression effector T cell function ( 26 ).…”

“…T-regulatory cells (Tregs) can proliferate in lactate-rich environments, which mediates suppression effector T cell function ( 26 ). In addition, feeding a HFD in carcinogen diethylnitrosamine (DEN)-injected promoted the development of HCC compared to mice fed a control diet, with increased secretion of lactate ( 25 ).…”