Biology subjects

N. Srinivas, A.

Publications and source records attributed to N. Srinivas, A..

3 recordsLinked to original sources

bioRxiv2024

Silencing of Hepatic AATF Ameliorates Metabolic Dysfunction Associated Steatohepatitis by Promoting Fatty Acid β-Oxidation in Experimental models

Background & aimsMetabolic dysfunction-associated steatohepatitis (MASH) is a multifactorial disease driven by complex molecular mechanisms. Identifying key regulators is critical for developing targeted therapies. Here, we demonstrate the impact of the loss of apoptosis antagonizing transcription factor (AATF) on hepatic lipid metabolism and MASH progression. MethodsA preclinical mouse model recapitulating human MASH was established by feeding C57Bl/6 mice either a chow diet (CD) or a western diet with sugar water (WD). Hepatic AATF silencing was achieved by tail vein injection of siAATF delivered by adeno-associated virus 8 (AAV8) with the liver-specific thyroxine-binding globulin (TBG) promoter. In addition to histological, biochemical, and molecular biology evaluations, the mechanistic insights were derived from whole transcriptomics and untargeted metabolomics analyses. ResultsAAV8-mediated specific knockdown of AATF in hepatocytes significantly reduced body weight, liver weight, and insulin resistance in mice fed with western diet (WD). However, no such effects were observed in mice fed with a chow diet (CD). Further analyses showed reduced liver injury, steatosis, and steatohepatitis in WDsiAATF mice. Transcriptomic analysis demonstrated that loss of AATF alleviated cellular stress, inflammation, and fibrosis in WD-fed mice. Moreover, AATF silencing led to alterations in lipid metabolism, notably by decreasing hepatic lipogenesis in the WD mice. Interestingly, untargeted metabolomics revealed an increase in the biosynthesis of glycerophospholipids and beta-oxidation of fatty acids in WDsiAATF mice. ConclusionOur findings reveal a previously unrecognized role of AATF as a central regulator of hepatic lipid metabolism in MASH, acting through the AKT-mTORC1 signaling pathway, and establish its inhibition as a promising therapeutic strategy for metabolic liver disease.

molecular biology↗

bioRxiv2024

Green Jackfruit Flour Prevents Metabolic Dysfunction-Associated Steatohepatitis and Progression to Hepatocellular Carcinoma via the AMPK and MAPK Signaling Pathways

Metabolic dysfunction-associated steatotic liver disease (MASLD), encompassing metabolic-dysfunction associated steatotic liver (MAFL) and steatohepatitis (MASH), which further progresses to hepatocellular carcinoma (HCC), is a serious public health concern. Given the paucity of approved therapeutic strategies for this lifestyle disorder, dietary interventions may prove effective. We evaluated how green jackfruit flour (JF) prevents MASH and progression to HCC and its underlying mechanisms. The study utilized two murine models that mimicked human MASLD disease: (i) a diet-induced MASH model; (ii) a MASH-HCC model induced by diet and a very low dose of CCl4. C57Bl/6 mice were fed with chow (CD) or western diet (WD) with normal (NW) or sugar water (SW) for 12 weeks, then randomized to receive either 5 kcal% green jackfruit flour (JF) or an equal volume of placebo flour (PB). The biochemical, histological, and molecular analyses were assessed. JF significantly reduced body weight, liver injury, insulin resistance, and alleviated obesity, steatosis, inflammation, fibrosis, and tumor development in WDSW or WDSW/CCl4 mice compared to placebo groups. Furthermore, JF activated AMPK (AMP-activated protein kinase) and inhibited MAPK (mitogen-activated protein kinase) signaling pathways in MASH and MASH-HCC experimental models, respectively. This was supported by sodium propionate treatment, the primary short-chain fatty acid entering the liver from JFs soluble fiber microbial fermentation, which also regulated AMPK and MAPK signaling in cellular models of MASH and HCC, respectively. Hence, our findings present strong evidence of JFs therapeutic potential in the prevention of MASH and MASH-HCC, warranting further investigation of JFs efficacy as a dietary intervention in clinical trials.

cancer biology↗

bioRxiv2023

Curcumin Ameliorates AATF-mediated Liver Damage and Inflammation to Cancer in NASH-HCC

In tandem with the expanding obesity pandemic, the prevalence of metabolic dysfunction associated steatohepatitis (MASH, formerly known as NASH)-driven hepatocellular carcinoma (HCC) is predicted to rise globally, creating a significant need for therapeutic interventions. We previously identified the upregulation of apoptosis antagonizing transcription factor (AATF), which is implicated in facilitating the progression from MASH to HCC. The objective of this study was to examine whether the intervention of curcumin could alleviate AATF-mediated MASH, inhibit tumor growth, and elucidate the underlying mechanism. A preclinical murine model mimicking human MASH-HCC was employed, subjecting mice to either a chow diet normal water (CDNW) or western diet sugar water (WDSW) along with very low dose of carbon tetrachloride (CCl4-0.2 l/g, weekly). Mice receiving curcumin (CUR) alongside WDSW/CCl4 exhibited significant improvements, including reduced liver enzymes, dyslipidemia, steatosis, inflammation, and hepatocellular ballooning. Curcumin treatment also suppressed hepatic expression of inflammatory, fibrogenic, and oncogenic markers. Of note, there was a significant reduction in the expression of AATF upon curcumin treatment in WDSW/CCl4 mice and human HCC cells. In contrast, curcumin upregulated Kruppel-like factor 4 (KLF4) in MASH liver and HCC cells, which is known to downregulate sp1 (specificity protein-1) expression. Thus, curcumin treatment effectively inhibited the progression of MASH to HCC by downregulating the expression of AATF via the KLF4-Sp1 signaling pathway. These preclinical findings establish a novel molecular connection between curcumin and AATF in reducing hepatocarcinogenesis, and provide a strong rationale for the development of curcumin as a viable treatment for MASH-HCC in humans.

cancer biology↗