High carbohydrate diet induces acute liver injury, enhanced de novo lipogenesis, inflammation and fibrosis but reversible by M2 macrophage polarization

We have studied the accretion of lipids in growing mice. We measured the rates of synthesis and degradation of triglycerides in epididymal fat pads of mice maintained for 44 days on a low-fat, high-carbohydrate diet ( I) or a high-fat, lowcarbohydrate diet ( II). 2H2O was added to the drinking water for 14 days. Rates of incorporation/washout of 2H to/from C1 of triglyceride-glycerol showed that triglyceride synthesis was greater than triglyceride degradation (net triglyceride balance was ∼2.5 times greater in II than in I). The data also show that the contribution of de novo lipogenesis to triglyceride-bound palmitate was ∼3 times greater in I than in II. This was consistent with a greater relative intake of carbohydrate in I vs. II. The rates of incorporation and washout of newly synthesized (2H-labeled) palmitate into and from triglycerides were also measured. Those data suggested a remodeling of triglyceride-bound fatty acids. On measuring the profile of triglyceride-bound fatty acids, we observed a decrease in the relative abundance of triglyceride-bound palmitate and stearate and an increase in triglyceride-bound oleate and linoleate. This was observed in I and II. In summary, diet substantially affects the deposition and modeling of triglycerides in adipose tissue during growth. 2H2O can be used to examine the mechanisms responsible for the accumulation of triglycerides, e.g., factors that affect 1) triglyceride synthesis and degradation and 2) the source of fatty acids that are used in esterification.

Download Full-text

Effect of carbohydrate intake on de novo lipogenesis in human adipose tissue

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1987.253.6.e664 ◽

1987 ◽

Vol 253 (6) ◽

pp. E664-E669 ◽

Cited By ~ 5

Author(s):

C. Chascione ◽

D. H. Elwyn ◽

M. Davila ◽

K. M. Gil ◽

J. Askanazi ◽

...

Keyword(s):

Adipose Tissue ◽

De Novo ◽

Acid Synthesis ◽

De Novo Lipogenesis ◽

Whole Body ◽

High Intake ◽

Carbohydrate Diet ◽

Triglyceride Synthesis ◽

High Carbohydrate

Rates of synthesis, from [14C]glucose, of fatty acids (de novo lipogenesis) and glycerol (triglyceride synthesis) were measured in biopsies of adipose tissue from nutritionally depleted patients given low- or high-carbohydrate intravenous nutrition. Simultaneously, energy expenditure and whole-body lipogenesis were measured by indirect calorimetry. Rates of whole-body lipogenesis were zero on the low-carbohydrate diet and averaged 1.6 g.kg-1.day-1 on the high-carbohydrate diet. In vitro rates of triglyceride synthesis increased 3-fold going from the low to the high intake; rates of fatty acid synthesis increased approximately 80-fold. In vitro, lipogenesis accounted for less than 0.1% of triglyceride synthesis on the low intake and 4% on the high intake. On the high-carbohydrate intake, in vitro rates of triglyceride synthesis accounted for 61% of the rates of unidirectional triglyceride synthesis measured by indirect calorimetry. In vitro rates of lipogenesis accounted for 7% of whole-body lipogenesis. Discrepancies between in vitro rates of fatty acid synthesis from glucose, compared with acetate and citrate, as reported by others, suggest that in depleted patients on hypercaloric high-carbohydrate diets, adipose tissue may account for up to 40% of whole-body lipogenesis.

Download Full-text

A low-protein, high-carbohydrate diet increases de novo fatty acid synthesis from glycerol and glycerokinase content in the liver of growing rats

Nutrition Research ◽

10.1016/j.nutres.2013.04.010 ◽

2013 ◽

Vol 33 (6) ◽

pp. 494-502 ◽

Cited By ~ 19

Author(s):

Andreza Lúcia Menezes ◽

Mayara Peron Pereira ◽

Samyra Lopes Buzelle ◽

Maísa Pavani dos Santos ◽

Suélem Aparecida de França ◽

...

Keyword(s):

Fatty Acid ◽

Fatty Acid Synthesis ◽

De Novo ◽

Acid Synthesis ◽

High Carbohydrate Diet ◽

Carbohydrate Diet ◽

High Carbohydrate ◽

Growing Rats ◽

Low Protein

Download Full-text

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

Nutrition ◽

10.1016/j.nut.2020.110782 ◽

2020 ◽

Vol 75-76 ◽

pp. 110782 ◽

Cited By ~ 3

Author(s):

Simona Pompili ◽

Antonella Vetuschi ◽

Eugenio Gaudio ◽

Alessandra Tessitore ◽

Roberta Capelli ◽

...

Keyword(s):

Liver Injury ◽

Mouse Model ◽

High Fat Diet ◽

High Carbohydrate Diet ◽

High Fat ◽

Carbohydrate Diet ◽

High Carbohydrate

Download Full-text

A Benzenediamine Analog FC-99 Drives M2 Macrophage Polarization and Alleviates Lipopolysaccharide- (LPS-) Induced Liver Injury

Mediators of Inflammation ◽

10.1155/2019/7823069 ◽

2019 ◽

Vol 2019 ◽

pp. 1-9 ◽

Cited By ~ 2

Author(s):

Wei Gong ◽

Haiyan Zhu ◽

Li Lu ◽

Yayi Hou ◽

Huan Dou

Keyword(s):

Liver Injury ◽

Macrophage Polarization ◽

M2 Macrophage ◽

M1 Macrophage ◽

M2 Macrophage Polarization ◽

Underlying Mechanisms ◽

Sirna Knockdown ◽

Lower Expression ◽

Alternatively Activated

Macrophages have variable functional phenotypes, high diversity, and plasticity and are involved in the pathogenesis of sepsis-induced liver injury. Alteration of macrophage polarization through activated (M1) macrophage to alternatively activated (M2) macrophage has emerged as a potential therapeutic strategy. This study was designed to explore the effect of a benzenediamine analog FC-99 on macrophage polarization in vitro and lipopolysaccharide- (LPS-) induced liver injury followed by the underlying mechanisms. For in vitro experiments, FC-99 inhibited M1-related macrophage factors and promoted M2-related markers induced by IL-4 in the mouse macrophage cell line RAW264.7. Moreover, FC-99-induced macrophages polarized to M2 phenotype which could be repressed by a PPAR-γ inhibitor but not STAT6 siRNA knockdown, indicating FC-99-induced M2 macrophage polarization through PPAR-γ rather than STAT6 signal. In LPS-induced septic mice, FC-99 pretreated mice displayed lower expression of M1 markers together with the increased M2 marker CD206 and improvement of liver injury. These findings illustrated that FC-99 could promote M2 macrophage polarization via PPAR-γ signaling and seemed to be a potential therapeutic candidate for inflammatory liver injury.

Download Full-text

MCC950 Ameliorates Acute Liver Injury Through Modulating Macrophage Polarization and Myeloid-Derived Suppressor Cells Function

Frontiers in Medicine ◽

10.3389/fmed.2021.752223 ◽

2021 ◽

Vol 8 ◽

Author(s):

Wei Yan ◽

Yingchun Shen ◽

Jinny Huang ◽

Ling Lu ◽

Qian Zhang

Keyword(s):

Liver Injury ◽

Molecular Mechanisms ◽

Acute Liver Injury ◽

Macrophage Polarization ◽

Suppressor Cells ◽

Suppressor Cell ◽

Pathological Process ◽

M2 Macrophage ◽

Pyrin Domain ◽

M1 Macrophage

Acute liver injury (ALI) raises high mortality rates due to a rapid pathological process. MCC950, a highly selective nod-like receptor family pyrin domain containing 3 (NLRP3) inhibitor, has already been reported to show strong hepatoprotective effects in many different liver diseases. In this study, we unveiled the role of MCC950 in carbon tetrachloride (CCl4)-induced ALI and its underlying molecular mechanisms on days 1, 2, and 3. MCC950 could significantly inhibit liver injury, evidenced by decreased serum alamine aminotransferase (ALT) and aspartate aminotransferase (AST) levels on days 1 and 2, increased Albumin (ALB) level on day 3, and decreased histological score during the whole period. Moreover, lower M1 macrophage related to pro-inflammatory genes expression was observed in MCC950-treated ALI mice on day 1, while MCC950 pretreatment also polarized macrophage to M2 phenotype indicating anti-inflammatory response on days 2 and 3. Additionally, MDSC was significantly increased in blood, liver, and spleen in ALI mice at different time courses. Specifically, upregulated myeloid-derived suppressor cell (MDSC) proportions were found in blood and spleen on days 1 and 2, but showed decreased trend on day 3. However, liver MDSC numbers were increased on days 2 and 3, but no significance on day 1. In conclusion, MCC950 pretreatment alleviates CCl4-induced ALI through enhanced M2 macrophage and MDSC function at different time points of ALI. Further understanding of MCC950 in ALI may be a new potential therapeutic strategy.

Download Full-text