Emerging role of mammalian autophagy in ketogenesis to overcome starvation.

Autophagy is essential for the survival of lower organisms under conditions of nutrient depletion. However, whether autophagy plays a physiological role in mammals experiencing starvation is unknown. Ketogenesis is critical for overcoming starvation in mammals. We recently revealed that hepatic and renal autophagy are involved in starvation-induced ketogenesis, by utilizing tissue-specific autophagy-deficient mouse models. The liver is the principal organ to regulate ketogenesis, and a deficiency of liver-specific autophagy partially but significantly attenuates starvation-induced ketogenesis. While deficiency of renal-specific autophagy does not affect starvation-induced ketogenesis, mice with deficiency of both liver and kidney autophagy have even lower blood ketone levels and physical activity under starvation conditions than those lacking autophagy in the liver alone. These results suggest that the kidney can compensate for impaired hepatic ketogenesis. Since ketone bodies are catabolized from fatty acids, the uptake of fatty acids, the formation of intracellular lipid droplets, and fatty acid oxidation are critical for ketogenesis. We found that starvation-induced lipid droplet formation is impaired in autophagy-deficient organs. Thus, hepatic and renal autophagy are required for starvation-induced ketogenesis. This process is essential for maintaining systemic energy homeostasis and physical activity during starvation. Our findings provide a novel insight into mammalian autophagy and the physiology of starvation.

Mammalian autophagy is essential for hepatic and renal ketogenesis during starvation.

Autophagy is an intracellular degradation system activated, across species, by starvation. Although accumulating evidence has shown that mammalian autophagy is involved in pathogenesis of several modern diseases, its physiological role to combat starvation has not been fully clarified. In this study, we analysed starvation-induced gluconeogenesis and ketogenesis in mouse strains lacking autophagy in liver, skeletal muscle or kidney. Autophagy-deficiency in any tissue had no effect on gluconeogenesis during starvation. Though skeletal muscle- and kidney-specific autophagy-deficiency did not alter starvation-induced increases in blood ketone levels, liver-specific autophagy-deficiency significantly attenuated this effect. Interestingly, renal as well as hepatic expression of HMG-CoA synthase 2 increased with prolonged starvation. Furthermore, during starvation, mice lacking autophagy both in liver and kidney showed even lower blood ketone levels and physical activity than mice lacking autophagy only in liver. Starvation induced massive lipid droplet formation in extra-adipose tissues including liver and kidney, which was essential for ketogenesis. Moreover, this process was impaired in the autophagy-deficient liver and kidney. These findings demonstrate that hepatic and renal autophagy are essential for starvation-induced lipid droplet formation and subsequent ketogenesis and, ultimately, for maintaining systemic energy homeostasis. Our findings provide novel biological insights into adaptive mechanisms to combat starvation in mammals.

[Case of peritubular capillary dominant intravascular large B-cell lymphoma (PTC dominant IVLBCL) successfully treated with chemotherapy].

A 72-year-old woman developed common cold-like symptoms, diarrhea, a staggering gait, and persistent anorexia from the beginning of May 2009. In the middle of May, her general fatigue worsened, and she was transported to our hospital by ambulance. Abdominal CT showed bilateral renal enlargement, and her general condition and renal function rapidly deteriorated. The soluble interleukin-2 receptor (sIL-2R) level was elevated to 5,928 U/mL, and gallium scintigraphy showed a weak uptake in both kidneys. We considered the possibility of malignant lymphoma, and performed a renal biopsy, which showed no glomerular abnormalities, but disclosed the accumulation of large, atypical lymphoid cells with a high N/C ratio and dark chromatin in peritubular capillaries (PTC). On immunohistochemical staining, these atypical cells were found to be CD5(+), CD20 (+/-), CD10(-), CD3(-), and CD7(-), leading to a diagnosis of intravascular large B-cell lymphoma (IVLBCL). Since gallium scintigraphy showed no uptake in other organs, and examination of the cerebrospinal fluid and bone marrow revealed no tumor cells, the patient was considered to have kidney-limited IVLBCL. Chemotherapy was started immediately, which resulted in an improved general condition. Although her renal function deteriorated sufficiently to require dialysis, she was weaned from dialysis. After treatment with chemotherapy, the enlarged kidneys returned to the normal size. Subsequently, she has been receiving chemotherapy intermittently, and has remained free of recurrence. In general, IVLBCL mainly involving the kidney is difficult to diagnose antemortem, and is sometimes found at autopsy. We suggest that bilateral renal enlargement with renal failure of unknown origin should raise the suspicion of malignant lymphoma requiring a prompt renal biopsy. Cases of LBCL in which lymphoma cells fill PTC, as in this patient, have rarely been reported. We believe that this case is extremely valuable in understanding the pathogenesis of intravascular lymphoma invading the kidney; therefore, we report it with a review of the literature.

[Case of fanconi syndrome positive for anti-M2 antibodies revealed by severe hypokalemia and multiple bone fracture].

A 38-year-old female developed pain in the right leg in 2006. In 2007, the diagnosis of femoral head necrosis was made based on MR images, and femoral head prosthetic replacement was performed. In April 2009, she visited a local hospital for low back pain, and was referred to our department due to electrolyte abnormalities on hemanalysis. Since marked hypokalemia (K=2.5 mEq/L), hypophosphatemia, hyperchloric metabolic acidosis, proteinuria, and urinary blood sugar suggested Fanconi syndrome, she was admitted for close examination. Bone survey showed a marked decrease in the amount of bone particularly in the four limbs and fracture at the proximal 1/3 of the left ulnar bone. In the lumbar spine, scoliosis and vertebral deformity were observed. Since impaired P re-absorption and unselected aminoaciduria and osteomalacia were also present, the diagnosis of Fanconi syndrome was made. On admission, ventricular tachycardia developed due to hypokalemia, requiring immediate electrolyte correction. For differentiation from acquired Fanconi syndrome, various examinations were performed. No apparent cause was found except for the positive antimitochondrial antibody-M2 (anti-M2). In this case, no data suggested liver dysfunction, and subsequent liver biopsy also showed no significant pathological findings pointing to PBC. We encountered a patient with Fanconi syndrome positive for anti-M2. This case may attract interest, particularly in the mechanism of nephropathy due to anti-M2, and therefore, this case is reported with a literature review.