Retinoic acid signaling in fatty liver disease

Bawa, Fathima Nafrisha Cassim; Zhang, Yanqiao

doi:10.1016/j.livres.2023.07.002

Cited by 11 publications

(2 citation statements)

References 93 publications

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“…Therefore, it is possible that the effect of dietary vitamin A manipulation at the early stage of ALD is not evident, but may influence later stages of ALD. Indeed, it is well‐established that hepatic stellate cells are the primary storage site for hepatic vitamin A, and that depletion of their retinoid content is necessary for stellate cell activation and liver fibrosis (Bawa & Zhang, 2023; Blaner et al., 2009). Thus manipulating vitamin A status in a different ALD model that drives liver fibrosis may show an effect.…”

Section: Discussionmentioning

confidence: 99%

Modest effect of differential dietary vitamin A intake on the pathogenesis of alcohol‐associated liver disease

Ferdouse,

Clugston

2024

Alcohol, Clinical and Experimental Research

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BackgroundChronic alcohol consumption is a major public health issue. The primary organ damaged by alcohol abuse is the liver, leading to alcohol‐associated liver disease (ALD). ALD begins with hepatic steatosis and can progress to fibrosis and cirrhosis; however, we have an incomplete understanding of ALD pathogenesis. Interestingly, the liver is also the major organ for vitamin A metabolism and storage, and ALD has previously been linked with altered hepatic vitamin A homeostasis. We hypothesize that alcohol‐induced vitamin A depletion disrupts its normal function in the liver, contributing to the pathogenesis of ALD. To test this hypothesis, we postulated that adding copious vitamin A to the diet might alleviate ALD, and conversely, that a vitamin A deficient diet would worsen ALD.MethodsWe conducted two dietary intervention studies in mice comparing deficient (0 IU/g diet) and copious (25 IU/g diet) dietary vitamin A intake versus control (4 IU/g diet), using the NIAAA chronic‐binge model of ALD. Hepatic steatosis was assessed using histopathological and biochemical approaches. Tissue Vitamin A levels were measured using high‐performance liquid chromatography. Markers of ALD, hepatic inflammation and lipid metabolism were analyzed by the quantitative polymerase chain reaction and western blotting.ResultsAs expected, a 0 IU/g Vitamin A diet decreased, and a 25 IU/g Vitamin A diet increased hepatic Vitamin A stores. However, alcohol induced changes in hepatic triglyceride levels, markers of hepatic lipid metabolism, inflammation and fibrosis were not significantly different in mice consuming a copious or deficient vitamin A diet compared to control.ConclusionsAltered vitamin A intake and hepatic vitamin A storage have a minor effect on the pathogenesis of ALD. Thus, given the known link between altered retinoic acid signaling and ALD, future studies that further explore this linkage are warranted.

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Section: Discussionmentioning

confidence: 99%

Modest effect of differential dietary vitamin A intake on the pathogenesis of alcohol‐associated liver disease

Ferdouse,

Clugston

2024

Alcohol, Clinical and Experimental Research

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“…These CYP enzymes, thought to be involved in all-trans RA clearance, are members of the CYP26 family, including CYP26A1 and CYP26B1 [17,64]. Targeting RA signaling has been shown to be beneficial for humans, and numerous studies have demonstrated a relationship between the imbalance of RA and various liver diseases [13,15,16,[65][66][67][68][69]. The CYP1A1 enzyme plays a significant role in the conversion of procarcinogens into reactive metabolites and displayed a stronger up-regulation in four out of the five lots.…”

Section: Hepatocyte Transporters and Cytochrome P450 Enzymesmentioning

confidence: 99%

Probing Liver Injuries Induced by Thioacetamide in Human In Vitro Pooled Hepatocyte Experiments

Goel,

Printz,

Pannala

et al. 2024

IJMS

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Animal studies are typically utilized to understand the complex mechanisms associated with toxicant-induced hepatotoxicity. Among the alternative approaches to animal studies, in vitro pooled human hepatocytes have the potential to capture population variability. Here, we examined the effect of the hepatotoxicant thioacetamide on pooled human hepatocytes, divided into five lots, obtained from forty diverse donors. For 24 h, pooled human hepatocytes were exposed to vehicle, 1.33 mM (low dose), and 12 mM (high dose) thioacetamide, followed by RNA-seq analysis. We assessed gene expression variability using heat maps, correlation plots, and statistical variance. We used KEGG pathways and co-expression modules to identify underlying physiological processes/pathways. The co-expression module analysis showed that the majority of the lots exhibited activation for the bile duct proliferation module. Despite lot-to-lot variability, we identified a set of common differentially expressed genes across the lots with similarities in their response to amino acid, lipid, and carbohydrate metabolism. We also examined efflux transporters and found larger lot-to-lot variability in their expression patterns, indicating a potential for alteration in toxicant bioavailability within the cells, which could in turn affect the gene expression patterns between the lots. Overall, our analysis highlights the challenges in using pooled hepatocytes to understand mechanisms of toxicity.

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Adipocyte retinoic acid receptor α prevents obesity and steatohepatitis by regulating energy expenditure and lipogenesis

Cassim Bawa,

Hu,

Gopoju

et al. 2023

Obesity

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ObjectiveThe adipose tissue–liver axis is a major regulator of the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Retinoic acid signaling plays an important role in development and metabolism. However, little is known about the role of adipose retinoic acid signaling in the development of obesity‐associated NAFLD. In this work, the aim was to investigate whether and how retinoic acid receptor alpha (RARα) regulated the development of obesity and NAFLD.MethodsRARα expression in adipose tissue of db/db or ob/ob mice was determined. Rarαfl/fl mice and adipocyte‐specific Rarα−/− (RarαAdi−/−) mice were fed a chow diet for 1 year or high‐fat diet (HFD) for 20 weeks. Primary adipocytes and primary hepatocytes were co‐cultured. Metabolic regulation and inflammatory response were characterized.ResultsRARα expression was reduced in adipose tissue of db/db or ob/ob mice. RarαAdi−/− mice had increased obesity and steatohepatitis (NASH) when fed a chow diet or HFD. Loss of adipocyte RARα induced lipogenesis and inflammation in adipose tissue and the liver and reduced thermogenesis. In the co‐culture studies, loss of RARα in adipocytes induced inflammatory and lipogenic programs in hepatocytes.ConclusionsThe data demonstrate that RARα in adipocytes prevents obesity and NASH via inhibiting lipogenesis and inflammation and inducing energy expenditure.

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Retinoic acid signaling in fatty liver disease

Cited by 11 publications

References 93 publications

Modest effect of differential dietary vitamin A intake on the pathogenesis of alcohol‐associated liver disease

Modest effect of differential dietary vitamin A intake on the pathogenesis of alcohol‐associated liver disease

Probing Liver Injuries Induced by Thioacetamide in Human In Vitro Pooled Hepatocyte Experiments

Adipocyte retinoic acid receptor α prevents obesity and steatohepatitis by regulating energy expenditure and lipogenesis

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