Nonalcoholic fatty liver disease (NAFLD) is strongly associated with insulin resistance, obesity, and dyslipidemia. NAFLD encompasses a wide range of states from the simple accumulation of triglycerides in the hepatocytes to serious states accompanied by inflammation and fibrosis in the liver. De novo lipogenesis has been shown to be a significant factor in the development of hepatic steatosis in insulin-resistant states. Sterol regulatory element binding protein-1c (SREBP-1c) is the main transcription factor that mediates the activation of lipogenesis, and SREBP cleavage activating protein (SCAP) is required for the activation of SREBPs. Here, recent animal studies that suggest SCAP as a therapeutic target for hepatic steatosis and hypertriglyceridemia are discussed.

Liver fibrosis is a consequence of chronic liver injury associated with chronic viral infection, alcohol abuse, and nonalcoholic fatty liver. The evidence from clinical and animal studies indicates that transforming growth factor-β (TGF-β) signaling is associated with the development of liver fibrosis. Krüppel-like factor 10 (KLF10) is a transcription factor that plays a significant role in TGF-β-mediated cell growth, apoptosis, and differentiation. In recent studies, it has been reported to be associated with glucose homeostasis and insulin resistance. In the present study, we investigated the role of KLF10 in the progression of liver disease upon a high-sucrose diet (HSD) in mice. Wild type (WT) and Klf10 knockout (KO) mice were fed either a control chow diet or HSD (50% sucrose) for eight weeks. Klf10 KO mice exhibited significant hepatic steatosis, inflammation, and liver injury upon HSD feeding, whereas the WT mice exhibited mild hepatic steatosis with no apparent liver injury. The livers of HSD-fed Klf10 KO mice demonstrated significantly increased endoplasmic reticulum stress, oxidative stress, and proinflammatory cytokines. Klf10 deletion led to the development of sucrose-induced hepatocyte cell death both in vivo and in vitro. Moreover, it significantly increased fibrogenic gene expression and collagen accumulation in the liver. Increased liver fibrosis was accompanied by increased phosphorylation and nuclear localization of Smad3. Here, we demonstrate that HSD-fed mice develop a severe liver injury in the absence of KLF10 due to the hyperactivation of the endoplasmic reticulum stress response and CCAAT/enhance-binding protein homologous protein (CHOP)-mediated apoptosis of hepatocytes. The current study suggests that KLF10 plays a protective role against the progression of hepatic steatosis into liver fibrosis in a lipogenic state.

Polyunsaturated fatty acids (PUFAs) have important functions in biological systems. The beneficial effects of dietary PUFAs against inflammatory diseases, cardiovascular diseases, and metabolic disorders have been shown. Studies using cancer cells have presented the anti-tumorigenic effects of docosahexaenoic acid (DHA), an n-3 PUFA, while arachidonic acid (AA), an n-6 PUFA, has been shown to elicit both pro- and anti-tumorigenic effects. In the current study, the anti-tumorigenic effects of AA were evaluated in HT-29 human colon cancer cells. Upon adding AA in the media, more than 90% of HT-29 cells died, while the MCF7 cells showed good proliferation. AA inhibited the expression of SREBP-1 and its target genes that encode enzymes involved in fatty acid synthesis. As HT-29 cells contained lower basal levels of fatty acid synthase, a target gene of SREBP-1, than that in MCF7 cells, the inhibitory effects of AA on the fatty acid synthase levels in HT-29 cells were much stronger than those in MCF-7 cells. When oleic acid (OA), a monounsaturated fatty acid that can be synthesized endogenously, was added along with AA, the HT-29 cells were able to proliferate. These results suggested that HT-29 cells could not synthesize enough fatty acids for cell division in the presence of AA because of the suppression of lipogenesis. HT-29 cells may incorporate more AA into their membrane phospholipids to proliferate, which resulted in ER stress, thereby inducing apoptosis. AA could be used as an anti-tumorigenic agent against cancer cells in which the basal fatty acid synthase levels are low.

Jean-Mathieu Berger and Young-Ah Moon. Mol. Cells 2021;44:116-25. https://doi.org/10.14348/molcells.2021.2147

Cancer, a leading cause of death worldwide, is not simply a genetic disease. The tumor microenvironment (TME), encompassing both cellular and acellular components, plays an important role in tumor ...

The development of colorectal cancer typically involves the accumulated influences of genetic alterations, medical issues, lifestyle, and diet. Dietary fatty acids appear to affect the tumorigenesis and progression of colorectal cancer. Despite conflicting results, the current consensus on the effects of very long-chain polyunsaturated fatty acids on colorectal cancer is that low levels of eicosapentaenoic acid and docosahexaenoic acid, and high levels of arachidonic acid are associated with an increased risk of colorectal cancer. Altered levels of arachidonic acid in membrane phospholipids can change the levels of prostaglandin E₂, which affect the biological activities of cancer cells in multiple stages. Arachidonic acid and other very long-chain polyunsaturated fatty acids can affect tumorigenesis in prostaglandin E₂-independent manners as well, including stabilization of β-catenine, ferroptosis, ROS generation, regulation of transcription factors, and de novo lipogenesis. Recent studies have revealed an association between the activities of enzymes synthesizing very long-chain polyunsaturated fatty acids and tumorigenesis and cancer progression, although the mechanisms are still unknown. In this study, PUFA effects on tumorigenesis, the endogenous very long-chain polyunsaturated fatty acid synthesis pathway, metabolites of arachidonic acid and their effects on tumorigenesis and progression of CRC, and current knowledge that supports the association of the enzymes involved in the polyunsaturated fatty acid synthesis pathway with colorectal cancer tumorigenesis and progression are reviewed.