Regulation and targeting of SREBP-1 in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is an increasing burden on global public health and is associated with enhanced lipogenesis, fatty acid uptake, and lipid metabolic reprogramming. De novo lipogenesis is under the control of the transcription factor sterol regulatory element-binding protein 1 (SREBP-1) and essentially contributes to HCC progression. Here, we summarize the current knowledge on the regulation of SREBP-1 isoforms in HCC based on cellular, animal, and clinical data. Specifically, we (i) address the overarching mechanisms for regulating SREBP-1 transcription, proteolytic processing, nuclear stability, and transactivation and (ii) critically discuss their impact on HCC, taking into account (iii) insights from pharmacological approaches. Emphasis is placed on cross-talk with the phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt)-mechanistic target of rapamycin (mTOR) axis, AMP-activated protein kinase (AMPK), protein kinase A (PKA), and other kinases that directly phosphorylate SREBP-1; transcription factors, such as liver X receptor (LXR), peroxisome proliferator-activated receptors (PPARs), proliferator-activated receptor γ co-activator 1 (PGC-1), signal transducers and activators of transcription (STATs), and Myc; epigenetic mechanisms; post-translational modifications of SREBP-1; and SREBP-1-regulatory metabolites such as oxysterols and polyunsaturated fatty acids. By carefully scrutinizing the role of SREBP-1 in HCC development, progression, metastasis, and therapy resistance, we shed light on the potential of SREBP-1-targeting strategies in HCC prevention and treatment.

Iron(III)-salophene catalyzes redox cycles that induce phospholipid peroxidation and deplete cancer cells of ferroptosis-protecting cofactors

“…By providing reducing equivalents, NADPH regenerates GSH from glutathione disulfide (GSSG) via glutathione reductase, reduces oxidized thioredoxin via thioredoxin reductase [ 89 ], and reactivates catalase that has been inactivated by H 2 O 2 [ 93 ]. As a central redox cofactor for reductive anabolic reactions, NADPH is also involved in fatty acid [ 94 ], steroid [ 95 ], amino acid, and nucleotide biosynthesis [ 96 ] and the mevalonate pathway [ 95 ], all of which are interestingly linked to ferroptosis [ 1 , 7 , [97] , [98] , [99] , [100] ], but also to other cell death programs, particularly apoptosis [ [101] , [102] , [103] ]. However, NADPH is a double-edged sword and, as a co-substrate of POR or NADPH oxidase isoenzymes, also contributes to lipid peroxidation and cell death under certain conditions [ 11 , 12 , 104 ].…”

Silybin A fromSilybum marianumreprograms lipid metabolism to induce a cell fate-dependent class switch from triglycerides to phospholipids

“…While the transfer of fatty acids into lipid droplets contributes to the detoxification of excess free fatty acids 14 , a chronic increase in the number and size of lipid droplets induces hepatocyte enlargement and dysfunction 10,15 . This continuous lipid accumulation leads to hepatic steatosis and, as the disease progresses, to cirrhosis and hepatocellular carcinoma 2,16 . As an adaptive strategy to protect hepatocytes from lipid overload, autophagy of lipid droplets (lipophagy) is initiated 17 and the mobilized fatty acids are subjected to oxidative degradation 18 .…”