Recently, abnormality of metabolism and nutrition and life style-related disease including obesity is reported to be closely related to non-alcoholic fatty liver disease (NAFLD). About five to twenty-five percentage of NALFD progresses to cirrhosis for five to ten years, and in these patients with cirrhosis, hepatocarcinogenesis is occurred in ten percentage for five years. We reported the results of basic and clinical studies. Currently, we are studying the pathogenesis of each cell units composed live such as hepatocytes, endothelial cells, stellate cells and immune cells focused on the concepts of inflammation cell society or cancer echo-system.

In WHO collaborating center for chronic hepatitis and liver cancer designated in 2017, we are collaborating with WHO West-Pacific Region based on two term of reference, (1) To support WHO in reaching country specific screening, care and treatment milestones and targets of the Regional Action Plan for Viral Hepatitis in the Western Pacific 2016-2020, (2) To assist WHO in providing technical consultation, support, advice and training in the field of chronic hepatitis and liver cancer management to study public health intervention to hepatic diseases.

Alzheimer’s disease:
Heat-shock protein70.1 (Hsp70.1), as a means of molecular chaperone and lysosomal stabilizer, is a potent survival protein that confers cell protection against diverse stimuli, but its depletion induces neurodegeneration via lysosomal rupture and autophagy failure. In response to hydroxynonenal (HNE) being generated from ω-6 linoleic acid in the cooking oil by deep-frying, a specific oxidative injury ‘carbonylation’ occurs at the key site Arg469 of Hsp70.1. Carbonylated Hsp70.1 is easily cleaved by calpain which was activated during acute ischemia of stroke and chronic ischemia due to ageing. G protein-coupled receptor 40 (GPR40), a receptor for diverse non-esterified (free) fatty acids, is expressed predominantly in the brain and pancreas. GPR40 induces Ca2+ mobilization to reveal dual (beneficial and detrimental) effects in the brain for adult neurogenesis and stroke as well as in the pancreas for insulin secretion and type 2 diabetes. Oxidative stress-induced carbonylation of Hsp70.1, in coordination with the excessive GPR40 and calpain activation, leads to lysosomal rupture and release of cathepsins with the resultant neuronal death. Simultaneously, autophagy failure due to Hsp70.1 dysfunction causes storage of garbage proteins such as amyloid β and phosphorylated tau. In this project, we will study implication of HNE for neuronal death, using the tissue samples of monkeys, which underwent serial injection. of HNE (3~5 mg/W x 24W). Hsp70.1. HNE or GPR40 are candidates for both elucidating the mechanism of neuronal death and developing the therapeutic strategy for Alzheimer’s disease.

Lifestyle-related diseases:
Although excessive consumption of deep-fried foods and/or high-fat diets is regarded as the most important epidemiological factors of lifestyle diseases, the underlying mechanism remains grossly unknown. In another project, we will study whether the oxidized cooking oil may cause diverse cell degeneration/death for lifestyle diseases. Deep-fried foods cooked by ω-6 oil contain or intrinsically generate hydroxynonenal by peroxidation. Hydroxynonenal promotes carbonylation of Hsp70.1 protein, with the resultant impaired ability of cells to recycle damaged proteins and stabilize the lysosomal membrane. Until now, the mechanism of autophagy/lysosomal failure during ω-6 oil consumption for the occurrence of cell degeneration is not reported. As the ‘calpain-cathepsin hypothesis’ has been documented as a cause of ischemic neuronal death, its relevance to Alzheimer neuronal death was recently suggested with particular attentions to hydroxynonenal. However, its relevance to cell death of the hypothalamus, liver, and pancreas, being related to the appetite/energy control, is unknown. The hypothalamus senses information from both adipocyte-derived leptin and circulating free fatty acids. Levels of circulating fatty acids and hydroxynonenal are increased in obese subjects. As overactivation of fatty acid receptor GPR40 in response to excessive or oxidized fatty acids may lead to the disruption of Ca2+ homeostasis, it should be evaluated whether GPR40 overactivation contributes to diverse cell death. Accordingly, we will study the molecular implication of vegetable oil-derived hydroxynonenal for the lysosomal destabilization in non-alcoholic steatohepatitis (NASH), type 2 diabetes and obesity. We aim at elucidating whether similar cascade of the ‘calpain-mediated cleavage of carbonylated Hsp70.1’ can impair brain-lipid sensing to cause diverse cell injury of hypothalamus, liver and pancreas.

Our research focused on