Biology subjects

Suvarna, D.

Publications and source records attributed to Suvarna, D..

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↗

bioRxiv2022

Tecomella undulata Improves Insulin Sensitivity by Attenuating Inflammation and Oxidative Stress in Experimental NASH

Background and AimThe pathophysiology of NASH is complex owing to its diverse pathological drivers, and until recently, there were no approved drugs for this disease. Tecomella undulata is a popular herbal medicine used to treat hepatosplenomegaly, hepatitis, and obesity. However, the potential role of Tecomella undulata in NASH has not yet been scientifically investigated. Experimental ProcedureMice fed with chow diet and normal water (CDNW) or western diet and sugar water (WDSW) for 12 weeks were randomized to receive vehicle control, Saroglitazar, or Tecomella undulata for an additional 12 weeks. Insulin resistance, lipid profiles, histological analysis, and liver enzymes were assessed. The oxidative stress, ER and inflammatory markers were determined by quantitative RT-PCR (qRT-PCR) and western blot analysis. Results and ConclusionThe administration of Tecomella undulata via oral gavage lowered body weight, insulin resistance, alanine transaminase (ALT), aspartate transaminase (AST), triglycerides, and total cholesterol in WDSW mice but had no effect on CDNW mice. Tecomella undulata improved steatosis, lobular inflammation, and hepatocyte ballooning and resolved NASH in WDSW mice. Furthermore, Tecomella undulata also alleviated the WDSW-induced ER stress and oxidative stress, enhanced antioxidant status, and thus reduced inflammation in the treated mice. Of note, these effects were on par with Saroglitazar, the approved drug used to treat human NASH and positive control used in the study. Thus, our findings indicate the potential of Tecomella undulata to ameliorate WDSW-induced steatohepatitis, and these preclinical data provide a strong rationale for assessing Tecomella undulata for the treatment of NASH in humans.

physiology↗