CPT2 downregulation adapts HCC to lipid-rich environment and promotes carcinogenesis via acylcarnitine accumulation in obesity

Abstract

In obesity-driven and NASH-driven HCC, metabolic reprogramming mediated by the downregulation of CPT2 enables HCC cells to escape lipotoxicity and promotes hepatocarcinogenesis.

An altered gene expression profile in tyramine-exposed intestinal cell cultures supports the genotoxicity of this biogenic amine at dietary concentrations

“…Some studies report a correlation between CPT2 repression and carcinogenesis. For instance, the repression of CPT2 in hepatocytes was reported to be associated with abnormal lipid accumulation due to the suppression of fatty acid ß-oxidation, inducing the malignant transformation of hepatocytes 20 and hepatocarcinogenesis 21 . It might therefore be speculated that the repression of CPT2 by tyramine also leads to abnormal lipid accumulation, perhaps contributing towards the malignant transformation of intestinal epithelial cells.…”

Aberrant lipid metabolism in hepatocellular carcinoma cells as well as immune microenvironment: A review

“…Research shows that in human steatohepatitic HCC (SH‐HCC), the expression of carnitine palmitoyltransferase 2 (CPT2), which converts acylcarnitine back to acyl‐CoA, is down‐regulated; subsequently, the marked accumulation of acylcarnitine species is detected, suggesting that the serum acylcarnitine levels may serve as a biomarker of HCC . More importantly, CPT2 down‐regulation suppresses the FAO pathway and enables HCC cells to escape from lipotoxicity to adapt to a lipid‐rich environment, which is achieved through inhibiting the Src‐mediated c‐Jun NH2‐terminal kinase (JNK) activation . Furthermore, oleoyl carnitine (AC18:1), the long‐chain acylcarnitine that accumulates through FAO suppression induced by CPT2 down‐regulation, enhances hepatocarcinogenesis through the signal transducer and activator of transcription 3 (STAT3)‐mediated acquisition of stem cell properties .…”

Lipid-rich environment: a key role promoting carcinogenesis in obesity-related non-alcoholic fatty liver disease

“…A hallmark of NAFLD and HCC is the disrupted lipid metabolism. Fujiwara et al 5 provide a new mechanism that links lipid accumulation with carcinogenesis in NAFLD and explain, at least in part, the fact of finding steatohepatitis features within the neoplastic tissue in the so-called ‘steatohepatitic-HCC’, highly associated with underlying steatohepatitis and metabolic syndrome 6…”

“…In obesity-related NAFLD, liver lipid metabolism is already disrupted, and the enormous increased FA uptake coming from exogenous sources (diet or adipose tissue) contributes to the lipid-rich environment, which could be playing a role in carcinogenesis. Fujiwara et al 5 provide new insights in how, during obesity, in NAFLD-driven HCC, malignant cells adapt to the lipid-rich environment through downregulation of the carnitine palmitoyltransferase (CPT) 2, involved in mitochondrial FAO (figure 1). Related to mitochondrial FAO, activated long-chain FAs are converted, through CPT1, into acylcarnitines that will be transported across the inner membrane.…”

“…Then, CPT2 will turn them back to the corresponding acyl-CoAs, the substrates for mitochondrial FAO. Fujiwara et al 5 demonstrate that in obesity-related NAFLD-driven HCC, the decrease in CPT2 levels is linked to the accumulation of acylcarnitines in tissues and serum, which seems to be associated with decreased FAO. The authors also show that CPT2 knockdown suppresses palmitic acid (PA)-induced cell death in proliferating cells.…”