Isocaloric manipulation of macronutrients within a high-carbohydrate/moderate-fat diet induces unique effects on hepatic lipogenesis, steatosis and liver injury

Abstract

Diets containing excess carbohydrate and fat promote hepatic steatosis and steatohepatitis in mice. Little is known, however, about the impact of specific carbohydrate-fat combinations on liver outcome. This study was designed to determine whether high-energy diets with identical caloric density but different carbohydrate and fat composition have unique effects on the liver. Four experimental diets were formulated with 60% kcal carbohydrate and 20% kcal fat, each in nearly pure form from a single source: starch-oleate, starch-palmitate, sucrose-oleate and sucrose-palmitate. The diets were fed to mice for 3 or 12 wk for analysis of lipid metabolism and liver injury. Results All mice developed hepatic steatosis over 12 wk, but mice fed the sucrose-palmitate diet accumulated more hepatic lipid than those in the other 3 experimental groups. The exaggerated lipid accumulation in sucrose-palmitate-fed mice was attributable to a disproportionate rise in hepatic de novo lipogenesis. These mice accrued more hepatic palmitate and exhibited more evidence of liver injury than any of the other experimental groups. Interestingly, lipogenic gene expression in mice fed the custom diets did not correlate with actual de novo lipogenesis. In addition, de novo lipogenesis rose in all mice between 3 and 12 wk, without feedback inhibition from hepatic steatosis. Summary The pairing of simple sugar (sucrose) and saturated fat (palmitate) in a high-carbohydrate/moderate-fat diet induces more de novo lipogenesis and liver injury than other carbohydrate-fat combinations. Conclusion Diet-induced liver injury correlates positively with hepatic de novo lipogenesis and is not predictable by isolated analysis of lipogenic gene expression.

Male apoE*3-Leiden.CETP mice on high-fat high-cholesterol diet exhibit a biphasic dyslipidemic response, mimicking the changes in plasma lipids observed through life in men

“…This is in line with other mouse studies where high‐fat diet stimulated hepatic de novo lipogenesis and this effect was stronger with longer time spent on high‐fat diet (Pierce et al. ). In human studies, the relation between age and hepatic de novo lipogenesis has received little attention to date, with one study reporting increased hepatic de novo lipogenesis in elderly compared to younger controls (Flannery et al.…”

Dietary Macronutrient Composition Determines the Contribution of DGAT1 to Alcoholic Steatosis

“…The link between the low‐fat diet and de novo lipogenesis rests in the fact that this diet has a relatively high‐carbohydrate content compared to the high‐fat diet. Indeed, others have shown that a high‐carbohydrate diet will produce greater steatosis than a high‐fat diet, with corresponding markers of increased hepatic de novo lipogenesis (Li et al., ; Pierce et al., ; Schwarz et al., ). Thus, in our model, we propose that increased carbohydrate flux into the liver serves as a substrate for de novo lipogenesis, with the resultant fatty acids channeled toward TG synthesis catalyzed by DGAT2.…”

“…Follow‐up studies using both high‐ and low‐fat liquid diets led us to focus on potential mechanistic differences in the induction of alcoholic steatosis in mice consuming alcohol as part of diets with different fat content. While it is known that diets with different macronutrient composition can contribute differently to nonalcoholic fatty liver disease (NAFLD; Li et al., ; Pierce et al., ), to our knowledge this has not been previously explored at the molecular level in the context of liquid diet consumption and alcoholic hepatic steatosis.…”

LRH-1 regulates hepatic lipid homeostasis and maintains arachidonoyl phospholipid pools critical for phospholipid diversity

“…Scraped TG bands were hydrolyzed and FA methyl esters were formed by incubating in 3 N HCl in methanol (MilliporeSigma) at 65°C for 1 hours. FA methyl esters were extracted and derivatives were analyzed for deuterium enrichment by gas chromatography/mass spectrometry as described previously (53,54).…”