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Lipid deposition in the liver is associated with metabolic disorders including fatty liver disease, type II diabetes, and hepatocellular cancer. The enzymes acetyl-CoA carboxylase 1 (ACC1) and ACC2 are powerful regulators of hepatic fat storage; therefore, their inhibition is expected to prevent the development of fatty liver. In this study we generated liver-specific ACC1 and ACC2 double knockout (LDKO) mice to determine how the loss of ACC activity affects liver fat metabolism and whole-body physiology. Characterization of LDKO mice revealed unexpected phenotypes of increased hepatic triglyceride and decreased fat oxidation. We also observed that chronic ACC inhibition led to hyper-acetylation of proteins in the extra-mitochondrial space. In sum, these data reveal the existence of a compensatory pathway that protects hepatic fat stores when ACC enzymes are inhibited. Furthermore, we identified an important role for ACC enzymes in the regulation of protein acetylation in the extra-mitochondrial space.

Compared to normal cells, tumour cells exhibit an upregulation of glucose transporters and an increased rate of glycolytic activity. In previous research, we successfully identified a promising hit compound BH10 through a rigorous screening process, which demonstrates a potent capacity for inhibiting cancer cell proliferation by targeting glucose metabolism. In the current study, we identify Kelch-like ECH-associated protein 1 (Keap1) as a potential protein target of BH10via avidin pull-down assays with biotinylated-BH10. Subsequently, we present a comprehensive analysis of a series of BH10 analogues characterized by the incorporation of a naphthoimidazole scaffold and the introduction of a triazole ring with diverse terminal functional groups. Notably, compound 4d has emerged as the most potent candidate, exhibiting better anti-cancer activities against HEC1A cancer cells with an IC 50 of 2.60 μM, an extended biological half-life, and an improved pharmacokinetic profile (compared to BH10) in mice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

High fructose diets are associated with an increased risk of liver cancer. Previous studies in mice suggest increased lipogenesis is a key mechanism linking high fructose diets to liver tumour growth. However, these studies administered fructose to mice at supraphysiological levels. The aim of this study was to determine whether liver tumour growth and lipogenesis were altered in mice fed fructose at physiological levels. To test this, we injected male C57BL/6 mice with the liver carcinogen diethylnitrosamine and then fed them diets without fructose or fructose ranging from 10 to 20 % total calories. Results showed mice fed diets with ≥15 % fructose had significantly increased liver tumour numbers (2-4-fold) and total tumour burden (∼7-fold) vs mice fed no-fructose diets. However, fructose-associated tumour burden was not associated with lipogenesis. Conversely, unbiased metabolomic analyses revealed bile acids were elevated in the sera of mice fed a 15 % fructose diet vs mice fed a no-fructose diet. Using a syngeneic ectopic liver tumour model, we show that ursodeoxycholic acid, which decreases systemic bile acids, significantly reduced liver tumour growth in mice fed the 15 % fructose diet but not mice fed a no-fructose diet. These results point to a novel role for systemic bile acids in mediating liver tumour growth associated with a high fructose diet. Overall, our study shows fructose intake at or above normal human consumption (≥15 %) is associated with increased liver tumour numbers and growth and that modulating systemic bile acids inhibits fructose-associated liver tumour growth in mice., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Metabolic disorders such as type 2 diabetes, fatty liver disease, hyperlipidemia, and obesity commonly co-occur but clinical treatment options do not effectively target all disorders. Calorie restriction, semaglutide, rosiglitazone, and mitochondrial uncouplers have all demonstrated efficacy against one or more obesity-related metabolic disorders, but it currently remains unclear which therapeutic strategy best targets the combination of hyperglycaemia, liver fat, hypertriglyceridemia, and adiposity. Herein we performed a head-to-head comparison of 5 treatment interventions in the female db/db mouse model of severe metabolic disease. Treatments included ∼60 % calorie restriction (CR), semaglutide, rosiglitazone, BAM15, and niclosamide ethanolamine (NEN). Results showed that BAM15 and CR improved body weight and liver steatosis to levels superior to semaglutide, NEN, and rosiglitazone, while BAM15, semaglutide, and rosiglitazone improved glucose tolerance better than CR and NEN. BAM15, CR, semaglutide, and rosiglitazone all had efficacy against hypertriglyceridaemia. These data provide a comprehensive head-to-head comparison of several key treatment strategies for metabolic disease and highlight the efficacy of mitochondrial uncoupling to correct multiple facets of the metabolic disease milieu in female db/db mice., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kyle Hoehn reports financial support was provided by National Institutes of Health and National Health and Medical Research Council. Kyle Hoehn reports a relationship with Uncoupler Therapeutics, Inc. that includes: board membership and equity or stocks. Kyle Hoehn reports a relationship with Life Biosciences, Inc. that includes: equity or stocks. Kyle Hoehn has a patent via University of Virginia. Webster Santos reports financial support was provided by National Institutes of Health. Webster Santos reports a relationship with Uncoupler Therapeutics, Inc. that includes: board membership and equity or stocks. Webster Santos reports a relationship with Life Biosciences, Inc. that includes: equity or stocks., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The human genome is pervasively transcribed and approximately 98% of the genome is non-coding. Long non-coding RNAs (lncRNAs) are a heterogeneous group of RNA transcripts that are >200 nucleotides in length with minimal to no protein-coding potential. Similar to proteins, lncRNAs have important biological functions in both normal cells and disease states including many types of cancer. This review summarizes recent advances in our understanding of lncRNAs in cancer biology and highlights the potential for lncRNA as diagnostic biomarkers and therapeutics. Herein we focus on the poorly understood role of lncRNAs in endometrial cancer, the most common gynecologic malignancy in the developed world., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background & Aims: Mice exposed to the hepatocellular carcinogen diethylnitrosamine at 2 weeks of age have a high risk of developing primary liver tumors later in life. Previous studies have demonstrated that diethylnitrosamine-treated mice have increased tumor burden when fed an obesigenic "Western" diet rich in lard fat and sugar. However, the role of dietary fats vs. sugars in the promotion of liver cancer is poorly understood. The aim of this study was to determine how altering dietary fats vs. sugars affects tumor burden in the diethylnitrosamine model., Methods: C57BL/6N mice were treated with diethylnitrosamine at 2 weeks of age and, from 6 to 32 weeks of age, fed one of five diets that differed in fat and sugar content, including normal chow, ketogenic, and Western diets., Results: Mice fed sugar-rich diets had the greatest tumor burden irrespective of dietary fat content. In contrast, mice fed a high-fat low-sugar diet had the least tumor burden despite obesity and glucose intolerance. When evaluated as independent variables, tumor burden was positively correlated with hepatic fat accumulation, postprandial insulin, and liver IL-6, and inversely correlated with serum adiponectin. In contrast, tumor burden did not correlate with adiposity, fasting insulin, or glucose intolerance. Furthermore, mice fed high sugar diets had lower liver expression of p21 and cleaved caspase-3 compared to mice fed low sugar diets., Conclusions: These data indicate that dietary sugar intake contributes to liver tumor burden independent of excess adiposity or insulin resistance in mice treated with diethylnitrosamine., (Copyright © 2014 European Association for the Study of the Liver. All rights reserved.)

Insulin resistance is the prodrome of many metabolic diseases and identifying ways to correct this pathological condition is a major goal for medical research. The foremost barrier to the development of new treatments is that the precise etiology of insulin resistance is uncertain. Recent studies suggest that changes in mitochondrial structure or function drive this condition, however much of this evidence is circumstantial. This Signaling Networks in Focus article provides a brief overview of known and speculative regulatory intersections whereby mitochondrial dysfunction at the levels of lipid oxidation, oxidative stress, calcium, adenine nucleotides, and protons may regulate insulin sensitivity. If mitochondrial dysfunction underlies the origins of metabolic disease then determining the precise molecular pathway will be essential for the development of new treatment and prevention strategies., (Copyright © 2010 Elsevier Ltd. All rights reserved.)