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Osteopontin (OPN) expression correlates with tumor progression in many cancers, including hepatocellular carcinoma (HCC); however, its role in the onset of HCC remains unclear. We hypothesized that increased hepatocyte‐derived OPN is a driver of hepatocarcinogenesis. Analysis of a tissue microarray of 366 human samples revealed a continuous increase in OPN expression during hepatocarcinogenesis. In patients with cirrhosis, a transcriptome‐based OPN correlation network was associated with HCC incidence along 10 years of follow‐up, together with messenger RNA (mRNA) signatures of carcinogenesis. After diethylnitrosamine (DEN) injection, mice with conditional overexpression of Opn in hepatocytes (OpnHep transgenic [Tg]) showed increased tumor burden. Surprisingly, mice with conditional ablation of Opn in hepatocytes (OpnΔHep) expressed a similar phenotype. The acute response to DEN was reduced in OpnΔHep, which also showed more cancer stem/progenitor cells (CSCs, CD44+AFP+) at 5 months. CSCs from OpnHep Tg mice expressed several mRNA signatures known to promote carcinogenesis, and mRNA signatures from OpnHep Tg mice were associated with poor outcome in human HCC patients. Treatment with rOPN had little effect on CSCs, and their progression to HCC was similar in Opn−/− compared with wild‐type mice. Finally, ablation of Cd44, an OPN receptor, did not reduce tumor burden in Cd44−/−OpnHep Tg mice. Conclusions: Hepatocyte‐derived OPN acts as a tumor suppressor at physiological levels by controlling the acute response to DEN and the presence of CSCs, while induction of OPN is pro‐tumorigenic. This is primarily due to intracellular events rather that by the secretion of the protein and receptor activation. [ABSTRACT FROM AUTHOR]

Alcohol‐associated liver disease (ALD) is a significant clinical problem for which the most effective therapy is alcohol abstinence. The two aims of this study were, first, to identify the liver transcriptome, fecal microbiome, and portal serum metabolome at peak injury and during early and late resolution from ALD; and second, to integrate their interactions and understand better the pathogenesis of ALD. To provoke alcohol‐induced liver injury, female and male wild‐type mice were fed the control or ethanol Lieber‐DeCarli diets for 6 weeks. To study early and late resolution, alcohol was withdrawn from the diet and mice were sacrificed after 3 and 14 days, respectively. At peak injury, there was increased signal transducer and activator of transcription (Stat3), Rho‐GTPases, Tec kinase and glycoprotein VI (Gp6), and decreased peroxisome proliferator–activated receptor signaling. During resolution from ALD, there was up‐regulation of vitamin D receptor/retinoid X receptor, toll‐like receptor, p38 and Stat3, and down‐regulation of liver X receptor signaling. Females showed significant changes in catabolic pathways, whereas males increased cellular stress, injury, and immune‐response pathways that decreased during resolution. The bacterial genus Alistipes and the metabolite dipeptide glycyl‐L‐leucine increased at peak but decreased during resolution from ALD in both genders. Hepatic induction of mitogen‐activated protein kinase (Map3k1) correlated with changes in the microbiome and metabolome at peak but was restored during ALD resolution. Inhibition of MAP3K1 protected from ALD in mice. Conclusion: Alcohol abstinence restores the liver transcriptome, fecal microbiome, and portal serum metabolome in a gender‐specific manner. Integration of multiomics data identified Map3k1 as a key gene driving pathogenesis and resolution from ALD. [ABSTRACT FROM AUTHOR]

Hydrodynamic tail vein injection (HTV) is the "gold standard" for delivering naked DNA vectors to mouse liver, thereby transfecting predominately perivenous hepatocytes. While HTV corrects metabolic liver defects such as phenylketonuria or cystathionine β-synthase deficiency, correction of spf ash mice with ornithine transcarbamylase (OTC) deficiency was not possible despite overexpression in the liver, as the OTC enzyme is primarily expressed in periportal hepatocytes. To target periportal hepatocytes, we established hydrodynamic retrograde intrabiliary injection (HRII) in mice and optimized minicircle (MC) vector delivery using luciferase as a marker gene. HRII resulted in a transfection efficiency below 1%, 100-fold lower than HTV. While HRII induced minimal liver toxicity compared with HTV, overexpression of luciferase by both methods, but not of a natural liver-specific enzyme, elicited an immune response that led to the elimination of luciferase expression. Further testing of MC vectors delivered via HRII in spf ash mice did not result in sufficient therapeutic efficacy and needs further optimization and/or selection of the corrected cells. This study reveals that luciferase expression is toxic for the liver. Furthermore, physical delivery of MC vectors via the bile duct has the potential to treat defects restricted to periportal hepatocytes, which opens new doors for non-viral liver-directed gene therapy., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)

Recent controversy regarding the therapeutic potential of curcumin indicates the challenges to research in this field. Here, we highlight the investigations of curcumin and other plant-derived polyphenols that demonstrate their application to metabolic diseases, in particular, obesity and diabetes. Thus, a number of preclinical and clinical investigations have shown the beneficial effect of curcumin (and other dietary polyphenols) in attenuating body weight gain, improving insulin sensitivity, and preventing diabetes development in rodent models and prediabetic subjects. Other intervention studies with dietary polyphenols have also found improvements in insulin resistance. Recent studies suggest that the metabolic effects of curcumin/polyphenols are linked to changes in the gut microbiota. Thus, research into curcumin continues to provide novel insights into metabolic regulation that may ultimately translate into effective therapy.