Ablation of Hmgb1 in Intestinal Epithelial Cells Causes Intestinal Lipid Accumulation and Reduces NASH in Mice

Gaskell, Harriet; Ge, Xiaodong; Désert, Romain; Das, Subodh K.; Han, Hui; Lantvit, Daniel D.; Guzman, Grace; Nieto, Natalia

doi:10.1002/hep4.1448

Cited by 14 publications

(18 citation statements)

References 49 publications

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“…Adult-onset hepatocyte-specific PPARγ knockout ( Pparg ΔHep ) mice were generated by using 10-week-old chow-fed Pparg fl/fl mice with adeno-associated virus (AAV)-delivered Cre recombinase, whereas Pparg fl/fl mice treated with AAV-Null vector served as controls (see Methods). Two weeks later, a subset of mice in each group was fed a high fat, cholesterol, and fructose (HFCF) diet for 24 weeks to induce NASH 21 or a nutrient-matched low fat, cholesterol, and fructose (LFCF) diet. In male but not female mice, HFCF diet increased the expression of hepatic PPARγ, whereas Pparg ΔHep reduced and prevented the HFCF-mediated up-regulation of hepatic PPARγ expression ( Figure 1 A ).…”

Section: Resultsmentioning

confidence: 99%

Hepatocyte-Specific Loss of PPARγ Protects Mice From NASH and Increases the Therapeutic Effects of Rosiglitazone in the Liver

Lee

Pusec

Norris

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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Background & Aims Nonalcoholic steatohepatitis (NASH) is commonly observed in patients with type 2 diabetes, and thiazolidinediones (TZD) are considered a potential therapy for NASH. Although TZD increase insulin sensitivity and partially reduce steatosis and alanine aminotransferase, the efficacy of TZD on resolving liver pathology is limited. In fact, TZD may activate peroxisome proliferator-activated receptor gamma (PPARγ) in hepatocytes and promote steatosis. Therefore, we assessed the role that hepatocyte-specific PPARγ plays in the development of NASH, and how it alters the therapeutic effects of TZD on the liver of mice with diet-induced NASH. Methods Hepatocyte-specific PPARγ expression was knocked out in adult mice before and after the development of NASH induced with a high fat, cholesterol, and fructose (HFCF) diet. Results HFCF diet increased PPARγ expression in hepatocytes, and rosiglitazone further activated PPARγ in hepatocytes of HFCF-fed mice in vivo and in vitro. Hepatocyte-specific loss of PPARγ reduced the progression of HFCF-induced NASH in male mice and increased the benefits derived from the effects of TZD on extrahepatic tissues and non-parenchymal cells. RNAseq and metabolomics indicated that HFCF diet promoted inflammation and fibrogenesis in a hepatocyte PPARγ–dependent manner and was associated with dysregulation of hepatic metabolism. Specifically, hepatocyte-specific loss of PPARγ plays a positive role in the regulation of methionine metabolism, and that could reduce the progression of NASH. Conclusions Because of the negative effect of hepatocyte PPARγ in NASH, inhibition of mechanisms promoted by endogenous PPARγ in hepatocytes may represent a novel strategy that increases the efficiency of therapies for NAFLD.

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Section: Resultsmentioning

confidence: 99%

Hepatocyte-Specific Loss of PPARγ Protects Mice From NASH and Increases the Therapeutic Effects of Rosiglitazone in the Liver

Lee

Pusec

Norris

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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“…It is known that an HFCF diet induces human-like NASH with fibrosis in mice [13, 25]. Therefore, we assessed the extent of fibrosis by assessing picrosirius red/fast green stained liver sections ( Figure 6A ) and the expression of genes associated with fibrosis.…”

Section: Resultsmentioning

confidence: 99%

“…Two weeks later, half of the HFD-fed mice in each group (control and Pparg ΔHep ) were switched to a diet containing 40% kcal from fat (partially hydrogenated corn oil), 2% cholesterol (w/w), and 22% fructose (w/w) (HFCF diet, Cat #D16010101, Research Diets, Inc) for 16 additional weeks. HFCF diet induces NASH after 24 weeks in lean mice [13, 25]. This diet has a formula similar to the original AMLN diet [26] where trans-fat has been replaced with partially hydrogenated corn-oil.…”

Section: Methodsmentioning

confidence: 99%

Hepatocyte PPARγ contributes to the progression of non-alcoholic steatohepatitis in male and female obese mice

Lee

Muratalla

Karimi

et al. 2022

Preprint

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Background & AimsNon-alcoholic steatohepatitis (NASH) is associated with obesity and increased expression of hepatic peroxisome proliferator-activated receptor γ (PPARγ) in humans. Although we previously showed that the expression of PPARγ in hepatocytes contributes to the development NASH in lean mice, the relevance of hepatocyte PPARγ in the development of NASH associated with obesity is still poorly understood.MethodsHepatocyte PPARγ was knocked out (PpargΔHep) after the development of high-fat diet-induced obesity in male and female mice and before NASH was induced with a high fat, cholesterol and fructose (HFCF) diet. We assessed the effect of the diets and PpargΔHep on body composition and glucose homeostasis, as well as on the liver pathology, gene expression, and metabolome. In addition, liver biopsies from a cohort of 102 bariatric surgery patients were assessed for liver histology and gene expression.ResultsPPARγ expression, specifically PPARγ2, is mostly derived from hepatocytes and increased by high fat diets. PpargΔHep reduced HFCF-induced NASH progression without altering steatosis. Interestingly, PpargΔHep reduced the expression of key genes involved in hepatic fibrosis in HFCF-fed male and female mice, and collagen- stained fibrotic area in the liver of HFCF-fed male mice. In addition, transcriptomic and metabolomic data suggested that HFCF-diet regulated hepatic amino acid metabolism in a hepatocyte PPARγ-dependent manner. Specifically, PpargΔHep increased betaine-homocysteine methyltransferase expression and reduced homocysteine levels in HFCF- fed male mice. In a cohort of 102 bariatric surgery patients, 16 cases of NASH were associated with increased insulin resistance and hepatic PPARγ expression.ConclusionsHepatocyte PPARγ expression associated with obesity could regulate methionine metabolism and the progression of fibrosis in NASH.

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“…Those findings encouraged us to consider whether conditional impairment of chylomicron assembly might also reverse some of the key features in models of established NAFLD/NASH. We were further encouraged by other work showing that mice with intestine-specific deletion of high mobility group box 1 develop impaired intestinal lipid absorption with decreased chylomicron formation, yet were protected against diet-induced NASH ( 33 ).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of chylomicron assembly leads to dissociation of hepatic steatosis from inflammation and fibrosis

Newberry

Brunt

Ballentine

et al. 2021

Journal of Lipid Research

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Regulating dietary fat absorption may impact progression of nonalcoholic fatty liver disease (NAFLD). Here, we asked if inducible inhibition of chylomicron assembly, as observed in intestine-specific microsomal triglyceride (TG) transfer protein knockout mice ( Mttp-IKO ), could retard NAFLD progression and/or reverse established fibrosis in two dietary models. Mttp-IKO mice fed a methionine/choline-deficient (MCD) diet exhibited reduced hepatic TGs, inflammation, and fibrosis, associated with reduced oxidative stress and downstream activation of c-Jun N-terminal kinase and nuclear factor kappa B signaling pathways. However, when Mttp flox mice were fed an MCD for 5 weeks and then administered tamoxifen to induce Mttp-IKO , hepatic TG was reduced, but inflammation and fibrosis were increased after 10 days of reversal along with adaptive changes in hepatic lipogenic mRNAs. Extending the reversal time, following 5 weeks of MCD feeding to 30 days led to sustained reductions in hepatic TG, but neither inflammation nor fibrosis was decreased, and both intestinal permeability and hepatic lipogenesis were increased. In a second model, similar reductions in hepatic TG were observed when mice were fed a high-fat/high-fructose/high-cholesterol (HFFC) diet for 10 weeks, then switched to chow ± tamoxifen (HFFC → chow) or (HFFC → Mttp-IKO chow), but again neither inflammation nor fibrosis was affected. In conclusion, we found that blocking chylomicron assembly attenuates MCD-induced NAFLD progression by reducing steatosis, oxidative stress, and inflammation. In contrast, blocking chylomicron assembly in the setting of established hepatic steatosis and fibrosis caused increased intestinal permeability and compensatory shifts in hepatic lipogenesis that mitigate resolution of inflammation and fibrogenic signaling despite 50–90-fold reductions in hepatic TG.

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Ablation of Hmgb1 in Intestinal Epithelial Cells Causes Intestinal Lipid Accumulation and Reduces NASH in Mice

Cited by 14 publications

References 49 publications

Hepatocyte-Specific Loss of PPARγ Protects Mice From NASH and Increases the Therapeutic Effects of Rosiglitazone in the Liver

Hepatocyte-Specific Loss of PPARγ Protects Mice From NASH and Increases the Therapeutic Effects of Rosiglitazone in the Liver

Hepatocyte PPARγ contributes to the progression of non-alcoholic steatohepatitis in male and female obese mice

Inhibition of chylomicron assembly leads to dissociation of hepatic steatosis from inflammation and fibrosis

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