Long-term abuse of a high-carbohydrate diet is as harmful as a high-fat diet for development and progression of liver injury in a mouse model of NAFLD/NASH

Pompili, Simona; Vetuschi, Antonella; Gaudio, Eugenio; Tessitore, Alessandra; Capelli, Roberta; Alesse, Edoardo; Latella, Giovanni; Sferra, Roberta; Onori, Paolo

doi:10.1016/j.nut.2020.110782

Cited by 37 publications

(41 citation statements)

References 49 publications

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“…They begin to exhibit glucose intolerance, insulin resistance and hyperinsulinemia as early as 6 weeks of age, but does not spontaneously develop NASH/NAFLD [ 19 , 20 ]. Western (high fat) diet supplemented with fructose (WDF) has been reported to induce NASH/NAFLD in murine models [ 11 , 16 , 21 ]. When fed WDF, MS-NASH mice develop NAFLD/NASH phenotypes with elevation of plasma ALT/AST and lipid as early as 4 weeks, an increase in liver triglycerides ~ 12 weeks, and exhibition of hepatic steatosis, ballooning, inflammation and mild to moderate fibrosis ~ 20 weeks [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Carbon tetrachloride (CCl4) accelerated development of non-alcoholic fatty liver disease (NAFLD)/steatohepatitis (NASH) in MS-NASH mice fed western diet supplemented with fructose (WDF)

Zhang¹,

Wang

Chung³

et al. 2020

BMC Gastroenterol

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Background Multiple murine models of nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) have been established by using obesogenic diets and/or chemical induction. MS-NASH mouse (formally FATZO) is a spontaneously developed dysmetabolic strain that can progress from hepatosteatosis to moderate fibrosis when fed a western diet supplemented with 5% fructose (WDF). This study aimed to use carbon tetrachloride (CCl4) to accelerate and aggravate progression of NAFLD/NASH in MS-NASH mouse. Methods Male MS-NASH mice at 8 weeks of age were fed WDF for the entire study. Starting at 16 weeks of age, CCl4 was intraperitoneally administered twice weekly at a dose of 0.2 mL/kg for 3 weeks or 0.08 mL/kg for 8 weeks. Obeticholic acid (OCA, 30 mg/kg, QD) was administered in both MS-NASH and C57Bl/6 mice fed WDF and treated with CCl4 (0.08 mL/kg). Results WDF enhanced obesity and hepatosteatosis, as well as induced moderate fibrosis in MS-NASH mice similar to previous reports. Administration of CCl4 accelerated liver fibrosis with increased bridging and liver hydroxyproline contents, but had no significant impact on liver steatosis and lipid contents. High dose CCl4 caused high mortality and dramatic elevation of ALT and ASL, while low dose CCl4 resulted in a moderate elevation of ALT and AST with low mortality. Compared to C57BI/6 mice with WDF and CCl4 (0.08 mL/kg), MS-NASH mice had more prominent hepatosteatosis and fibrosis. OCA treatment significantly lowered liver triglycerides, steatosis and fibrosis in both MS-NASH and C57Bl/6 mice fed WDF with CCl4 treatment. Conclusions CCl4 reduced induction time and exacerbated liver fibrosis in MS-NASH mice on WDF, proving a superior NASH model with more prominent liver pathology, which has been used favorably in pharmaceutical industry for testing novel NASH therapeutics.

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Section: Introductionmentioning

confidence: 99%

Carbon tetrachloride (CCl4) accelerated development of non-alcoholic fatty liver disease (NAFLD)/steatohepatitis (NASH) in MS-NASH mice fed western diet supplemented with fructose (WDF)

Zhang¹,

Wang

Chung³

et al. 2020

BMC Gastroenterol

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“…[15]. However, Pompili et al showed that a high carbohydratelow fat diet was equally as harmful as a high fat diet alone [16].…”

Section: Risk Factors For Fibrosis Progressionmentioning

confidence: 99%

Natural Progression of Non-Alcoholic Steatohepatitis to Hepatocellular Carcinoma

et al. 2021

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Non-alcoholic steatohepatitis (NASH) is a chronic and progressive form of non-alcoholic fatty liver disease (NAFLD). Its global incidence is increasing which makes NASH an epidemic and a public health threat. Due to repeated insults to the liver, patients are at risk for developing hepatocellular carcinoma (HCC). The progression of NASH to HCC was initially defined according to a two-hit model which involved the development of steatosis, followed by lipid peroxidation and inflammation. However, current research defines a “multi-hit” or “multi-parallel hit” model which synthesizes several contributing pathways involved in progressive fibrosis and oncogenesis. This perspective considers the effects of cellular, genetic, immunologic, metabolic, and endocrine pathways leading up to HCC which underscores the complexity of this condition. This article will provide an updated review of the pathogenic mechanisms leading from NASH to HCC as well as an exploration of the role of biomarkers and screening.

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“…In physiological conditions, CLDs are temporarily accumulated in the cytosol of enterocytes as an energy reservoir and are released for energy supply during the intestinal fasting state [ 4 , 5 , 6 , 7 ]. However, when excessive accumulation of lipids occurs, as the result of an unbalanced diet or alterations in lipogenesis/lipolysis processes, severe diseases may result [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

Prolonged Chronic Consumption of a High Fat with Sucrose Diet Alters the Morphology of the Small Intestine

Sferra

Pompili

Cappariello

et al. 2021

IJMS

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(1) The high-fat diet (HFD) of western countries has dramatic effect on the health of several organs, including the digestive tract, leading to the accumulation of fats that can also trigger a chronic inflammatory process, such as that which occurs in non-alcohol steatohepatitis. The effects of a HFD on the small intestine, the organ involved in the absorption of this class of nutrients, are still poorly investigated. (2) To address this aspect, we administered a combined HFD with sucrose (HFD w/Suc, fat: 58% Kcal) regimen (18 months) to mice and investigated the morphological and molecular changes that occurred in the wall of proximal tract of the small intestine compared to the intestine of mice fed with a standard diet (SD) (fat: 18% Kcal). (3) We found an accumulation of lipid droplets in the mucosa of HFD w/Suc-fed mice that led to a disarrangement of mucosa architecture. Furthermore, we assessed the expression of several key players involved in lipid metabolism and inflammation, such as perilipin, leptin, leptin receptor, PI3K, p-mTOR, p-Akt, and TNF-α. All these molecules were increased in HFD mice compared to the SD group. We also evaluated anti-inflammatory molecules like adiponectin, adiponectin receptor, and PPAR-γ, and observed their significant reduction in the HFD w/Suc group compared to the control. Our data are in line with the knowledge that improper eating habits present a primary harmful assault on the bowel and the entire body’s health. (4) These results represent a promising starting point for future studies, helping to better understand the complex and not fully elucidated spectrum of intestinal alterations induced by the overconsumption of fat.

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Long-term abuse of a high-carbohydrate diet is as harmful as a high-fat diet for development and progression of liver injury in a mouse model of NAFLD/NASH

Cited by 37 publications

References 49 publications

Carbon tetrachloride (CCl4) accelerated development of non-alcoholic fatty liver disease (NAFLD)/steatohepatitis (NASH) in MS-NASH mice fed western diet supplemented with fructose (WDF)

Carbon tetrachloride (CCl4) accelerated development of non-alcoholic fatty liver disease (NAFLD)/steatohepatitis (NASH) in MS-NASH mice fed western diet supplemented with fructose (WDF)

Natural Progression of Non-Alcoholic Steatohepatitis to Hepatocellular Carcinoma

Prolonged Chronic Consumption of a High Fat with Sucrose Diet Alters the Morphology of the Small Intestine

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