Butyrate Protects against Diet-Induced NASH and Liver Fibrosis and Suppresses Specific Non-Canonical TGF-β Signaling Pathways in Human Hepatic Stellate Cells

Gart, Eveline; Duyvenvoorde, Wim van; Toet, Karin; Caspers, Martien P. M.; Verschuren, Lars; Nielsen, Mette Juul; Leeming, Diana Julie; Lima, Everton Souto; Menke, Aswin; Hanemaaijer, Roeland; Keijer, Jaap; Salic, Kanita; Kleemann, Robert; Morrison, Martine C.

doi:10.3390/biomedicines9121954

Cited by 27 publications

(17 citation statements)

References 47 publications

(70 reference statements)

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“…Intrahepatic concentrations of cytokines (IL-1b, IL-4, IL-6, IL-10, IL-15, IL-17A/F, IL-33, IFNy, and TNF-α) and chemokines (MIP1a/CCL3, IP10/CXL10, KC/CXCL1, MIP-2/CXCL2) were measured in liver biopsies homogenized in lysis buffer as previously reported. 32 The cytokines and chemokines in the liver were measured using a multiplex immunoassay panel (#KH152AOH; V-PLEX Custom Mouse Biomarker, Mesoscale Discovery [MSD], Maryland, USA) according to the manufacturer's protocol on a MESO QuickPlex SQ 120 reader (MSD). Total protein concentrations in the same homogenates were assessed with a BCA Protein Assay Kit (Thermo Fisher Scientific, Waltham, MA, USA) to determine the inflammatory factors per mg of protein.…”

Section: Intrahepatic Cytokines and Chemokinesmentioning

confidence: 99%

Intervention with isoleucine or valine corrects hyperinsulinemia and reduces intrahepatic diacylglycerols, liver steatosis, and inflammation in Ldlr−/−.Leiden mice with manifest obesity‐associated NASH

et al. 2022

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Non‐alcoholic steatohepatitis (NASH) is associated with a disturbed metabolism in liver, insulin resistance, and excessive accumulation of ectopic fat. Branched‐chain amino acids (BCAAs) may beneficially modulate hepatic lipids, however, it remains unclear whether individual BCAAs can attenuate already established NASH and associated oxidative‐inflammatory stress. After a 26 weeks run‐in on fast food diet (FFD), obese Ldlr−/−.Leiden mice were treated for another 12 weeks with either valine or isoleucine (3% of FFD) and then compared to FFD controls. Valine and isoleucine did not affect obesity, dyslipidemia, gut permeability, or fecal fatty acid excretion, but significantly reduced hyperinsulinemia. Valine and isoleucine reduced ALT, CK18‐M30, and liver steatosis with a particularly pronounced suppression of the microvesicular component (−61% by valine and −71% by isoleucine). Both BCAAs decreased intrahepatic diacylglycerols and 4‐hydroxynonenal immunoreactivity, a marker for oxidative stress‐induced lipid peroxidation. Functional genomics analysis demonstrated that valine and isoleucine affected BCAA metabolism genes, deactivated master regulators of anabolic pathways related to steatosis (e.g., SREBPF1), and activated master regulators of mitochondrial biogenesis (e.g., PPARGC1A) and lipid catabolism (e.g., ACOX1, AMPK). This correction of critical metabolic pathways on gene expression level was accompanied by a significant decrease in histological liver inflammation, and suppression of FFD‐stimulated cytokine and chemokine proteins KC/CXCL1, MCP‐1/CCL2, and MIP‐2/CXCL2 and their pathways. In conclusion, dietary intervention with either valine or isoleucine corrected liver diacylglycerols, gene expression of multiple metabolic processes, and reduced NASH histology with profound hepatoprotective effects on oxidative stress and inflammatory proteins.

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Section: Intrahepatic Cytokines and Chemokinesmentioning

confidence: 99%

Intervention with isoleucine or valine corrects hyperinsulinemia and reduces intrahepatic diacylglycerols, liver steatosis, and inflammation in Ldlr−/−.Leiden mice with manifest obesity‐associated NASH

et al. 2022

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“…Blood glucose was determined during blood sampling using a hand-held glucometer (Freestyle Freedom Light, Abbott Laboratories, Lake Bluff, IL, United States). Plasma insulin, leptin, adiponectin, cholesterol, triacylglycerols, ALT, CK-18M30 were determined as described (16). ELISA assays were used to measure plasma serum amyloid A (SAA; KMA0021 Thermo Fisher Scientific, Waltman, United States), MCP-1/CCL2 (DY479 R&D, Minneapolis, United States), MIF (DY1978 R&D, Fetuin A (DY1563 R&D) and LPS binding protein (LBP; HK205-02 Hycult Biotech, Uden, Netherlands) according to manufacturer's protocol.…”

Section: Blood Chemistrymentioning

confidence: 99%

“…RNA was isolated from livers (n = 18 HFD + vehicle and n = 18 HFD + 2 -FL) using RNA-Bee (Bio-Connect, Huissen, Netherlands) and purified using PureLink RNA Mini Kit (Thermo Fisher Scientific). RNA concentration was determined and RNA quality was assessed as reported in Gart et al (16). Strand-specific messenger RNA sequencing libraries for the Illumina (llumina NovaSeq6000, San Diego, CA, United States) platform were generated Paired-End 150 bp for approximately 20 million Paired-End reads per sample at Genomescan (Leiden, Netherlands).…”

Section: Gene Expression Analysis Using Next-generation Sequencing An...mentioning

confidence: 99%

The Human Milk Oligosaccharide 2′-Fucosyllactose Alleviates Liver Steatosis, ER Stress and Insulin Resistance by Reducing Hepatic Diacylglycerols and Improved Gut Permeability in Obese Ldlr-/-.Leiden Mice

et al. 2022

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Non-alcoholic fatty liver disease (NAFLD) is a complex multifactorial disorder that is associated with gut dysbiosis, enhanced gut permeability, adiposity and insulin resistance. Prebiotics such as human milk oligosaccharide 2′-fucosyllactose are thought to primarily improve gut health and it is uncertain whether they would affect more distant organs. This study investigates whether 2′-fucosyllactose can alleviate NAFLD development in manifest obesity. Obese hyperinsulinemic Ldlr-/-.Leiden mice, after an 8 week run-in on a high-fat diet (HFD), were treated with 2′-fucosyllactose by oral gavage until week 28 and compared to HFD-vehicle controls. 2′-fucosyllactose did not affect food intake, body weight, total fat mass or plasma lipids. 2′-fucosyllactose altered the fecal microbiota composition which was paralleled by a suppression of HFD-induced gut permeability at t = 12 weeks. 2′-fucosyllactose significantly attenuated the development of NAFLD by reducing microvesicular steatosis. These hepatoprotective effects were supported by upstream regulator analyses showing that 2′-fucosyllactose activated ACOX1 (involved in lipid catabolism), while deactivating SREBF1 (involved in lipogenesis). Furthermore, 2′-fucosyllactose suppressed ATF4, ATF6, ERN1, and NUPR1 all of which participate in endoplasmic reticulum stress. 2′-fucosyllactose reduced fasting insulin concentrations and HOMA-IR, which was corroborated by decreased intrahepatic diacylglycerols. In conclusion, long-term supplementation with 2′-fucosyllactose can counteract the detrimental effects of HFD on gut dysbiosis and gut permeability and attenuates the development of liver steatosis. The observed reduction in intrahepatic diacylglycerols provides a mechanistic rationale for the improvement of hyperinsulinemia and supports the use of 2′-fucosyllactose to correct dysmetabolism and insulin resistance.

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“…Leptin can modulate glucose and lipid metabolism and inhibit feed intake by directly acting on the central nervous system, which collectively regulates the metabolism of the host [ 40 ]. HFD usually induces elevated serum insulin and leptin levels [ 41 , 42 , 43 ], which are the indicators of insulin and leptin resistance, respectively, and risk factors for metabolic disorders [ 44 ]. Partial leptin reduction improved leptin and insulin sensitivity and decreased body weight in mice with HFD-induced obesity [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Depletion of Gut Microbiota Inhibits Hepatic Lipid Accumulation in High-Fat Diet-Fed Mice

Han

Wang

Zhong

et al. 2022

IJMS

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Dysregulated lipid metabolism is a key pathology in metabolic diseases and the liver is a critical organ for lipid metabolism. The gut microbiota has been shown to regulate hepatic lipid metabolism in the host. However, the underlying mechanism by which the gut microbiota influences hepatic lipid metabolism has not been elucidated. Here, a gut microbiota depletion mouse model was constructed with an antibiotics cocktail (Abx) to study the mechanism through which intestinal microbiota regulates hepatic lipid metabolism in high-fat diet (HFD)-fed mice. Our results showed that the Abx treatment effectively eradicated the gut microbiota in these mice. Microbiota depletion reduced the body weight and fat deposition both in white adipose tissue and liver. In addition, microbiota depletion reduced serum levels of glucose, total cholesterol (TC), low-density lipoproteins (LDL), insulin, and leptin in HFD-fed mice. Importantly, the depletion of gut microbiota in HFD-fed mice inhibited excessive hepatic lipid accumulation. Mechanistically, RNA-seq results revealed that gut microbiota depletion changed the expression of hepatic genes involved in cholesterol and fatty acid metabolism, such as Cd36, Mogat1, Cyp39a1, Abcc3, and Gpat3. Moreover, gut microbiota depletion reduced the abundance of bacteria associated with abnormal metabolism and inflammation, including Lachnospiraceae, Coriobacteriaceae_UCG-002, Enterorhabdus, Faecalibaculum, and Desulfovibrio. Correlation analysis showed that there was strong association between the altered gut microbiota abundance and the serum cholesterol level. This study indicates that gut microbiota ameliorates HFD-induced hepatic lipid metabolic dysfunction, which might be associated with genes participating in cholesterol and fatty acid metabolism in the liver.

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Butyrate Protects against Diet-Induced NASH and Liver Fibrosis and Suppresses Specific Non-Canonical TGF-β Signaling Pathways in Human Hepatic Stellate Cells

Cited by 27 publications

References 47 publications

Intervention with isoleucine or valine corrects hyperinsulinemia and reduces intrahepatic diacylglycerols, liver steatosis, and inflammation in Ldlr−/−.Leiden mice with manifest obesity‐associated NASH

Intervention with isoleucine or valine corrects hyperinsulinemia and reduces intrahepatic diacylglycerols, liver steatosis, and inflammation in Ldlr−/−.Leiden mice with manifest obesity‐associated NASH

The Human Milk Oligosaccharide 2′-Fucosyllactose Alleviates Liver Steatosis, ER Stress and Insulin Resistance by Reducing Hepatic Diacylglycerols and Improved Gut Permeability in Obese Ldlr-/-.Leiden Mice

Depletion of Gut Microbiota Inhibits Hepatic Lipid Accumulation in High-Fat Diet-Fed Mice

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