-This review showed the common pathogenic mechanism in the development of non-alcoholic or alcoholic steatohepatitis. In particular, we describe the role of innate immune system and oxidative stress caused by gut-derived endotoxin. Gut-derived endotoxin plays an important role in alcoholic liver injury. It was reported that acute ethanol administration reduced activation of Kupffer cells. It is therefore possible that alcohol-induced hepatocellular damage occurs as a result of bacterial or endotoxin translocation under a reduction of the reticuloendothelial system (RES) function in alcoholic liver disease (ALD). On the other hand, recently, attention has been directed toward the effect of ethanol ingestion on Kupffer cell function, which is stimulated by gut-derived endotoxin via mechanisms dependent on increased gut permeability and the possible relationship between Kupffer cells and alcohol-induced liver injury. It is generally accepted that activation of the innate immune system and increased release of proinflammatory cytokines and other mediators plays an important role in the development of ALD. It was shown that Kupffer cells activation by endotoxin via Toll-like receptor (TLR-4) is involved in alcoholinduced liver injury and that ethanol-induced oxidative stress is important in the regulation of transcription factor NF-κB activation and that cytokine production by Kupffer cells. TNF-α and free radicals are produced in early alcohol-induced liver injury. In support of this finding, the pathology caused by alcohol was blocked nearly completely in TNF-α receptor 1. Many pathways have been suggested to contribute to the ability of ethanol to induce a state of oxidative stress. One central pathway appears to be the induction of the CYP2E1 form of cytochrome P450 enzymes by ethanol. Initial efforts to clarify the mechanisms that promote the progression from steatosis to steatohepatitis somewhat artificially divides disease mechanisms into "first and second" hit. The best candidates for these second hits were considered to be oxidative stress (CYP2E1 induction) and associated lipid peroxidation and cyokines, principally, TNF-α. Some of the most definitive data on the importance of the innate immune system or oxidative stress in the pathogenesis of liver disease come from studies of alcoholic and non-alcoholic steatohepatitis in animals.

The quality of fat is an important factor in defining the quality of meat. Fat quality is determined by the composition of fatty acids. Among lipid metabolism-related genes, including fatty acid synthesis genes, several genetic variations have been reported in the bovine fatty acid synthase (FASN), stearoyl-CoA desaturase (SCD), sterol regulatory element-binding protein 1 (SREBP1), and GH genes. In the present study, we evaluated the single and epistatic effects of 5 genetic variations (4 SNP and 1 insertion/deletion) in 4 genes (FASN, SCD, SREBP1, and GH) on the fatty acid composition of the longissimus thoracis muscle and carcass and meat quality traits in 480 commercial Japanese Black cattle. Significant single effects of FASN, SCD, and GH(L127V) polymorphisms on the fatty acid composition of the longissimus thoracis muscle were detected. The A293V polymorphism of SCD had the largest effect on myristic acid (C14:0, P < 0.001), myristoleic acid (C14:1, P < 0.001), stearic acid (C18:0, P < 0.001), oleic acid (C18:1, P < 0.001), and MUFA (P < 0.001). Polymorphisms in the FASN, SCD, and SREBP1 genes showed no effect on any meat yield trait. There were no significant epistatic effects on fatty acid composition among pairs of the 3 genes (FASN, SCD, and SREBP1) involved in fatty acid synthesis. No epistatic interactions (P > 0.1) were detected between FASN and SCD for any carcass trait. When the genotypes of 3 markers (FASN, SCD, and GH(L127V)) were substituted from the lesser effect allele to the greater effect allele, the proportion of C18:1 increased by 4.46%. More than 20% of the genetic variance in the C18:1 level could be accounted for by these 3 genetic markers. The present results revealed that polymorphisms in 2 fatty acid synthesis genes (FASN and SCD) independently influenced fatty acid composition in the longissimus thoracis muscle. These results suggest that SNP in the FASN and SCD genes are useful markers for the improvement of fatty acid composition in commercial Japanese Black cattle.

Growing evidence indicates that the innate immune system and oxidative stress caused by gut-derived endotoxins play a key role in alcoholic liver disease (ALD). Intracellular mechanisms associated with endotoxin-induced signaling play a crucial role in the initiation and progression of ALD. It is now widely accepted that activation of the innate immune system and increased release of pro-inflammatory cytokines and other mediators play an important role in the development of ALD. Accumulating evidence suggests that alcohol-mediated upregulation of CYP2E1 expression may initiate lipid peroxidation via reactive oxygen species. Non-alcoholic steatohepatitis (NASH) is a liver disease characterized by histopathological features similar to those observed in ALD, but in the absence of significant alcohol consumption. Initial efforts to clarify the mechanisms that promote the progression from steatosis to steatohepatitis somewhat artificially divided disease mechanisms into "first and second hits." This model considered the development of steatosis to be the "first hit," increasing the sensitivity of the liver to the putative "second hit," leading to hepatocyte injury, inflammation, and oxidative stress. We have emphasized the important role of gut-derived bacterial toxins, the innate immune system, and oxidative stress in the common pathogenic mechanism in ALD and NASH progression.

This review describes the role of oxidative stress caused by endotoxin challenge in sepsis or septic shock symptoms. We observed that endotoxin injection resulted in lipid peroxide formation and membrane damage (near 60-150 kDa) in the livers of experimental animals, causing decreased levels of scavengers or quenchers of free radicals. The administration of a-tocopherol completely prevented injury to the liver plasma membrane caused by endotoxin, and suggested that lipid peroxidation by free radicals might occur in a tissue ischemic state, probably by disseminated intravascular coagulation (DIC), in endotoxemia. In mice, depression of Ca 21 -ATPase activity in the liver plasma membrane may contribute to the membrane damage caused by endotoxin, and the increase of [Ca 21 ] i in the liver cytoplasm may partially explain the oxidative stress that occurs in endotoxemia. It seems that endotoxin-induced free radical formation is regulated by Ca 21 mobilization. Moreover, we have suggested that the oxidative stress caused by endotoxin may be due, at least in part, to the changes in endogenous zinc or selenium regulation during endotoxemia. Interestingly, the extent of TNF-a-induced oxidative stress may be the result of a synergism between TNF-a and gut-derived endotoxin. It is likely that bacterial or endotoxin translocation plays a significant role in TNF-ainduced septic shock. On the other hand, although nitric oxide (NO) has been implicated in the pathogenesis of vascular hyporesponsiveness and hypotension in septic shock in our experimental model, it is unlikely that NO plays a significant role in liver injury caused by free radical generation in endotoxemia.

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