Mice in the early stage of liver steatosis caused by a high fat diet are resistant to thioacetamide-induced hepatotoxicity and oxidative stress

- Mice that were fed a high fat diet (HFD) developed a partial resistance to thioacetamide.
- Feeding a menhaden oil-containing HFD was more effective than feeding a lard-rich HFD.
- Lipid-loaded cells developed a partial resistance to hydrogen peroxide.
- Accumulated lipids appeared to partially protect against oxidative stress.

Lipogenesis is stimulated in the liver by an unfolded protein response (UPR) to endoplasmic reticulum stress under a variety of pathological conditions and results in the accumulation of lipids in hepatocytes. Assuming that UPR is a protective mechanism against stress, we hypothesized that the accumulated lipids might have a beneficial function. We prepared mice with fatty livers by feeding two types of high-calorie diets; a lard-rich high-calorie diet (LHD) or a menhaden oil-containing high-calorie diet (MHD), for two weeks and treated them, as well as control diet (CD)-fed mice, with thioacetamide (TAA), a liver toxicant. When a lethal dose (500 mg/kg) of TAA was administered, the LHD-fed mice and the MHD-fed mice survived longer than those fed with CD. The accumulated lipids appeared to be associated with protecting the liver against TAA toxicity (200 mg/kg). Consistently, lipid-loaded Hepa 1-6 cells showed a partial resistance to hydrogen peroxide toxicity compared to those cultured in conventional media. In conclusion, while sustained steatosis impairs liver function and leads to hazardous conditions, lipids that transiently accumulate as the result of UPR or other stimuli may exert a beneficial function in the liver at least partly through scavenging reactive oxygen species.

Schematic diagram of the effects of accumulated lipid in hepatocytes. Treatment with TAA or hydrogen peroxide caused oxidative damage to hepatocytes. Accumulated lipids in the cells were partly peroxidized but also caused the elimination of ROS. Thus, cellular damage are mitigated by the accumulated lipids at an early steatosis.95