A Translational Mouse Model for NASH with Advanced Fibrosis and Atherosclerosis Expressing Key Pathways of Human Pathology

Non-alcoholic steatohepatitis (NASH) is a fast-growing liver disorder that is associated with an increased incidence of cardiovascular disease and type 2 diabetes. Animal models adequately mimicking this condition are scarce. We herein investigate whether Ldlr−/−. Leiden mice on different high-fat diets represent a suitable NASH model. Ldlr−/−. Leiden mice were fed a healthy chow diet or fed a high-fat diet (HFD) containing lard or a fast food diet (FFD) containing milk fat. Additionally, the response to treatment with obeticholic acid (OCA) was evaluated. Both high-fat diets induced obesity, hyperlipidemia, hyperinsulinemia, and increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Mice on both diets developed progressive macro- and microvesicular steatosis, hepatic inflammation, and fibrosis, along with atherosclerosis. HFD induced more severe hyperinsulinemia, while FFD induced more severe hepatic inflammation with advanced (F3) bridging fibrosis, as well as more severe atherosclerosis. OCA treatment significantly reduced hepatic inflammation and fibrosis, and it did not affect atherosclerosis. Hepatic transcriptome analysis was compared with human NASH and illustrated similarity. The present study defines a translational model of NASH with progressive liver fibrosis and simultaneous atherosclerosis development. By adaptation of the fat content of the diet, either insulin resistance (HFD) or hepatic inflammation and fibrosis (FFD) can be aggravated.

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Black, pinto and white beans lower hepatic lipids in hamsters fed high fat diets by excretion of bile acids

Food Production, Processing and Nutrition ◽

10.1186/s43014-020-00039-5 ◽

2020 ◽

Vol 2 (1) ◽

Author(s):

Priscila L. S. Alves ◽

Jose De J Berrios ◽

James Pan ◽

Wallace H. Yokoyama

Keyword(s):

Lithocholic Acid ◽

Plasma Cholesterol ◽

Liver Cholesterol ◽

Control Group ◽

Chow Diet ◽

High Fat ◽

Bean Flour ◽

Freeze Dried ◽

High Fat Diets ◽

Fat Diets

Abstract Hypolipidemic and anti-obesity properties of extruded black, pinto and white beans were examined in male Syrian hamsters fed high fat diets for 3 weeks. The efficiency and effectiveness of extruder processing to eliminate heat-labile antinutrients were also determined. Hamsters fed a high fat diet containing 40% extruded black beans gained the same amount of weight as animals on a low-fat chow diet (based on AIN-93G). Total plasma cholesterol of the hamsters fed bean flour- based diets tended to be lower, ranging between 298 and 356 mg/dL, compared to 365 mg/dL for the control group and total and free liver cholesterol was about 50 and 33% lower, respectively, in the livers (freeze-dried) of hamsters fed the black turtle bean (BB) and pinto bean (PB) diets. The nitrogen content of the feces from hamsters fed the PB and white bean (WB) diets were 2.6x higher than the control and the excretion of deoxycholic acid (DCA) and lithocholic acid (LCA) was higher in all legume fed hamsters The results show that extrusion efficiently and economically reduces anti-nutritive factors that inhibit the digestion and absorption of proteins and carbohydrates. Graphical abstract

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The triglyceride synthesis enzymes DGAT1 and DGAT2 have distinct and overlapping functions in adipocytes

The Journal of Lipid Research ◽

10.1194/jlr.m093112 ◽

2019 ◽

Vol 60 (6) ◽

pp. 1112-1120 ◽

Cited By ~ 18

Author(s):

Chandramohan Chitraju ◽

Tobias C. Walther ◽

Robert V. Farese

Keyword(s):

Adipose Tissue ◽

High Fat Diet ◽

Convergent Evolution ◽

Metabolic Energy ◽

Chow Diet ◽

High Fat ◽

Functional Differences ◽

High Fat Diets ◽

Fat Stores ◽

Fat Diets

Mammals store metabolic energy as triacylglycerols (TGs) in adipose tissue. TG synthesis is catalyzed by the evolutionarily unrelated acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes DGAT1 and DGAT2, which catalyze the same reaction and account for nearly all TG synthesis. The reasons for their convergent evolution to synthesize TGs remain unclear. Mice lacking DGAT1 are viable with reduced fat stores of TGs, whereas DGAT2 KO mice die postnatally just after birth with >90% reduction of TGs, suggesting that DGAT2 is the predominant enzyme for TG storage. To better understand the functional differences between the DGATs, we studied mice fed chow or high-fat diets lacking either enzyme in adipose tissue. Unexpectedly, mice lacking DGAT2 in adipocytes have normal TG storage and glucose metabolism on regular or high-fat diets, indicating DGAT2 is not essential for fat storage. In contrast, mice lacking DGAT1 in adipocytes have normal TG storage on a chow diet but moderately decreased body fat accompanied by glucose intolerance when challenged with a high-fat diet. The latter changes were associated with the activation of ER stress pathways. We conclude that DGAT1 and DGAT2 can largely compensate for each other for TG storage but that DGAT1 uniquely has an important role in protecting the ER from the lipotoxic effects of high-fat diets.

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Effect of Dietary Vitamin E on Rumen Biohydrogenation Pathways and Milk Fat Depression in Dairy Cows Fed High-Fat Diets

Journal of Dairy Science ◽

10.3168/jds.s0022-0302(06)72131-2 ◽

2006 ◽

Vol 89 (2) ◽

pp. 685-692 ◽

Cited By ~ 66

Author(s):

J. Pottier ◽

M. Focant ◽

C. Debier ◽

G. De Buysser ◽

C. Goffe ◽

...

Keyword(s):

Vitamin E ◽

Dairy Cows ◽

Milk Fat ◽

Dietary Vitamin ◽

High Fat ◽

Milk Fat Depression ◽

High Fat Diets ◽

Fat Diets

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Effect of high fat diets on the performance, milk yield and milk composition of multiparous rabbit does

Animal Science ◽

10.1017/s1357729800050177 ◽

1999 ◽

Vol 68 (1) ◽

pp. 151-162 ◽

Cited By ~ 24

Author(s):

J. J. Pascual ◽

C. Cervera ◽

E. Blas ◽

J. Fernández-Carmona

Keyword(s):

Milk Yield ◽

Minimum Temperature ◽

Milk Fat ◽

Energy Content ◽

Control Diet ◽

Milk Composition ◽

High Fat ◽

Litter Weight ◽

High Fat Diets ◽

Fat Diets

AbstractExperiment I. One hundred and twenty-five lactations from 88 New Zealand × Californian does were used to study the influence of high fat diets on the performance and milk yield of multiparous rabbit does in two high productivity situations: housed in hot conditions (minimum temperature above 24°C) with eight pups (group H8), or housed in warm conditions (minimum temperature under 21 °C) with 11 pups (group W11). Starting from a control diet (diet C) with 26 g ether extract (ЕЕ) per kg dry matter (DM), two isoenergetic diets were formulated adding fat from vegetable sources up to 99 g ЕЕ per kg DM (diet V) or animal sources up to 117 g ЕЕ per kg DM (diet A). The lactating does showed similar food daily intakes (⋍105 g DM per kg), therefore digestible energy intake of does on high fat diets was significantly higher (P < 0·001). The addition of f at to the diets increased (P < 0·001) milk yield of does (+21 and 24 g/day for diets V and A, respectively) and litter weight at weaning (P < 0·05), and decreased the number of pups replaced (P < 0·01) during lactation. Group H8 does had significantly lower DM intakes, litter growth rates and milk production levels than group Wll does (P < 0·001).Experiment 2. The effect of these diets on milk composition was determined in 62 lactations from 28 multiparous rabbit does, in which litter size was maintained at eight pups. Milk samples were collected manually on the 7th, 21st and 28th days of lactation. Milk of does given high fat diets, especially diet A, had higher fat and energy contents (P < 0·001) and a lower protein content (P < 0·001) than those given diet C. Milk of does given diet A had a greater DM content than those given the diets С or V (P < 0·001). There was a correlation between the fatty acid composition of milk and dietary fat. The proportion of odd chain fatty acids in the milk fat was lower for does given diet V (P < 0·05) than those given diet A. In conclusion, high fat diets were related to a higher milk yield and energy content of milk, allowing a higher litter weight gain and a lower mortality of sucking pups.

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The relationship between plasma lipid composition and milk fat secretion in cows given diets containing soybean oil

Journal of Dairy Research ◽

10.1017/s0022029900013686 ◽

1971 ◽

Vol 38 (1) ◽

pp. 57-64 ◽

Cited By ~ 16

Author(s):

W. Steele ◽

R. C. Noble ◽

J. H. Moore

Keyword(s):

Fatty Acids ◽

Soybean Oil ◽

Milk Fat ◽

Cholesteryl Esters ◽

Total Plasma ◽

High Fat ◽

Plasma Triglycerides ◽

High Fat Diets ◽

Concentrate Mixture ◽

Fat Diets

SummaryThe effects on the composition of the plasma lipids of the isocaloric replacement of starch in a low-fat concentrate mixture by 8 % soybean oil were investigated in a feeding experiment with 6 cows in mid-lactation. Two high-fat concentrate mixtures were given: in one, the soybean oil was incorporated into the diet by the inclusion of the appropriate amount of coarsely ground soybeans; in the other, the soybean oil was incorporated directly in the concentrate mixture. The concentrate mixtures were given with a high-roughage diet that supplied daily 5·5kg hay and 2·7kg of sugar-beet pulp.When the cows were given the 2 high-fat diets there were increases in the concentrations of total plasma fatty acids and in the concentrations of fatty acids circulating in the plasma as phospholipids and cholesteryl esters. There were increases in the concentrations of plasma unesterified fatty acids and triglyceride fatty acids when the cows were given the diet containing soybeans but there were decreases in the concentrations of these 2 fractions when the cows were given the diet containing soybean oil.The inclusion of soybeans in the diet increased the concentration of 18:0 in the plasma triglycerides and unesterified fatty acids whilst the inclusion of soybean oil in the diet increased the concentrations of 18:0 and 18:1 but decreased the concentration of 18:2 in the plasma unesterified fatty acids.When the cows were given the 2 high-fat diets there were decreases in the concentrations of 16:0 and 16:1 and increases in the concentration of 18:2 in the plasma cholesteryl esters. The inclusion of soybeans in the diet also reduced the concentrations of 18:1 and 20:3 in the plasma cholesteryl esters but increased the concentrations of 18:0 and 18:2 in the plasma phospholipids.The major fatty acid circulating in the plasma of the cows was 18:2 (46·4–55·3%) on all diets but only about 1% (0·40–1·04%) of the total plasma 18:2 occurred in the plasma triglycerides.The results are discussed in relation to the changes in the composition of the milk fatty acids produced by the cows when they were given the experimental diets.

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The effects of supplements containing different carbohydrate sources on milk production in cows receiving a hay-based diet

Proceedings of the British Society of Animal Production (1972) ◽

10.1017/s0308229600019097 ◽

1990 ◽

Vol 1990 ◽

pp. 129-129

Author(s):

P.A. Martin ◽

D.G. Chamberlain ◽

S. Robertson

Keyword(s):

Milk Production ◽

Milk Fat ◽

Weight Basis ◽

Long Chain Fatty Acids ◽

High Fat ◽

Fresh Weight ◽

Fresh Weight Basis ◽

Citrus Pulp ◽

High Fat Diets ◽

Fat Diets

There are well established differences in the digestion characteristics of the carbohydrate sources available for inclusion in rations for dairy cows, but the implications of these differences for milk production remain poorly defined. The experiment reported here was conducted to compare 4 concentrates containing contrasting carbohydrate types, namely sources of readily-fermentable starch (barley), of sugar, of starch that is fermented relatively slowly in the rumen such that some is absorbed as glucose from the small intestine (maize) and of sugar and digestible fibre (citrus pulp). Given the advantages of dietary inclusion of appropriate fats as a means of increasing the energy density of the ration and/or of producing ‘less-saturated’ milk fat, and the likelihood that responses to high-fat diets would be modified by carbohydrate type, the different carbohydrate sources were compared in concentrates containing a high proportion of fat (16% on a fresh weight basis) as calcium salts of long-chain fatty acids.

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Non-Fasting Factor VII Coagulant Activity (FVII:C) Increased by High-Fat Diet

Thrombosis and Haemostasis ◽

10.1055/s-0038-1642518 ◽

1994 ◽

Vol 71 (06) ◽

pp. 755-758 ◽

Cited By ~ 46

Author(s):

E M Bladbjerg ◽

P Marckmann ◽

B Sandström ◽

J Jespersen

Keyword(s):

High Fat Diet ◽

Fat Content ◽

Factor Vii ◽

Amidolytic Activity ◽

High Fat ◽

Low Fat Diet ◽

Increased Risk ◽

Coagulant Activity ◽

High Fat Diets ◽

Fat Diets

SummaryPreliminary observations have suggested that non-fasting factor VII coagulant activity (FVII:C) may be related to the dietary fat content. To confirm this, we performed a randomised cross-over study. Seventeen young volunteers were served 2 controlled isoenergetic diets differing in fat content (20% or 50% of energy). The 2 diets were served on 2 consecutive days. Blood samples were collected at 8.00 h, 16.30 h and 19.30 h, and analysed for triglycerides, FVII coagulant activity using human (FVII:C) or bovine thromboplastin (FVII:Bt), and FVII amidolytic activity (FVIPAm). The ratio FVII:Bt/FVII:Am (a measure of FVII activation) increased from fasting levels on both diets, but most markedly on the high-fat diet. In contrast, FVII: Am (a measure of FVII protein) tended to decrease from fasting levels on both diets. FVII:C rose from fasting levels on the high-fat diet, but not on the low-fat diet. The findings suggest that high-fat diets increase non-fasting FVII:C, and consequently may be associated with increased risk of thrombosis.

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