High fat diet induces dysregulation of hepatic oxygen gradients and mitochondrial function in vivo

Abstract

NAFLD (non-alcoholic fatty liver disease), associated with obesity and the cardiometabolic syndrome, is an important medical problem affecting up to 20% of western populations. Evidence indicates that mitochondrial dysfunction plays a critical role in NAFLD initiation and progression to the more serious condition of NASH (non-alcoholic steatohepatitis). Herein we hypothesize that mitochondrial defects induced by exposure to a HFD (high fat diet) contribute to a hypoxic state in liver and this is associated with increased protein modification by RNS (reactive nitrogen species). To test this concept, C57BL/6 mice were pair-fed a control diet and HFD containing 35% and 71% total calories (1 cal≈4.184 J) from fat respectively, for 8 or 16 weeks and liver hypoxia, mitochondrial bioenergetics, NO (nitric oxide)-dependent control of respiration, and 3-NT (3-nitrotyrosine), a marker of protein modification by RNS, were examined. Feeding a HFD for 16 weeks induced NASH-like pathology accompanied by elevated triacylglycerols, increased CYP2E1 (cytochrome P450 2E1) and iNOS (inducible nitric oxide synthase) protein, and significantly enhanced hypoxia in the pericentral region of the liver. Mitochondria from the HFD group showed increased sensitivity to NO-dependent inhibition of respiration compared with controls. In addition, accumulation of 3-NT paralleled the hypoxia gradient in vivo and 3-NT levels were increased in mitochondrial proteins. Liver mitochondria from mice fed the HFD for 16 weeks exhibited depressed state 3 respiration, uncoupled respiration, cytochrome c oxidase activity, and mitochondrial membrane potential. These findings indicate that chronic exposure to a HFD negatively affects the bioenergetics of liver mitochondria and this probably contributes to hypoxic stress and deleterious NO-dependent modification of mitochondrial proteins.

Omega-3 Fatty Acid Improve Non Alcoholic Fatty Liver Induced by High Fat Diet in Rats.

“…The observation of the current study was in accordance with those of the previous studies [21,22]which reported that there is an elevation of both triglycerides and NEFA in NAFLD in rats. The mechanisms governing the accumulation of TGs in hepatic cells include changes in hepatocellular metabolism, [23,24] propagating an imbalance between uptake and de novo fatty acid synthesis, VLDL formation and subsequent export, and oxidation capacity [25].The present study also revealed that treatment with omega-3 fatty acid showed significant reduction in the level of triglycerides and NEFA in plasma compared to those of HFD treated group. This is in agreement with the previous [26,27]which supports the triglyceride-lowering properties of omega-3 fatty acid and decreased NEFA level in plasma.…”

Abnormal hepatic energy homeostasis in type 2 diabetes

“…Increased circulating lipids derived from dietary intake and impaired inhibition of lipolysis stimulate lipid oxidation and production of reactive oxygen species, giving rise to lipid peroxidation and damage of mitochondrial proteins and DNA, reduction of oxidative capacity, and subsequent lipid accumulation. 42,43 In support of this contention, patients with NASH exhibit paracrystalline inclusions in megamitochondria, 11,44 increased mitochondrial DNA mutations, 45 and lower respiratory complex activities in the liver. 20 But even obese subjects already may have lower liver ATP resynthesis upon fructose administration.…”

Does Simple Steatosis Affect Liver Regeneration after Partial Hepatectomy in Rats?

“…NAFLD is associated with mitochondrial oxidative alterations (12), increased production of reactive oxygen and nitrogen species and decreased liver content of reduced glutathione (GSH) (13,14). Accumulating evidence indi- 36 cates that mitochondrial dysfunction participates as a key player in the pathophysiology of NAFLD (15).…”