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Hepatic gluconeogenesis from amino acids contributes significantly to diabetic hyperglycemia, but the molecular mechanisms involved are incompletely understood. Alanine transaminases (ALT1 and ALT2) catalyze the interconversion of alanine and pyruvate, which is required for gluconeogenesis from alanine. We find that ALT2 is overexpressed in the liver of diet-induced obese and db/db mice and that the expression of the gene encoding ALT2 (GPT2) is downregulated following bariatric surgery in people with obesity. The increased hepatic expression of Gpt2 in db/db liver is mediated by activating transcription factor 4, an endoplasmic reticulum stress-activated transcription factor. Hepatocyte-specific knockout of Gpt2 attenuates incorporation of

Adipocyte triglyceride storage provides a reservoir of energy that allows the organism to survive times of nutrient scarcity, but excessive adiposity has emerged as a health problem in many areas of the world. Monoacylglycerol acyltransferase (MGAT) acylates monoacylglycerol to produce diacylglycerol; the penultimate step in triglyceride synthesis. However, little is known about MGAT activity in adipocytes, which are believed to rely primarily on another pathway for triglyceride synthesis. We show that expression of the gene that encodes MGAT1 is robustly induced during adipocyte differentiation and that its expression is suppressed in fat of genetically-obese mice and metabolically-abnormal obese human subjects. Interestingly, MGAT1 expression is also reduced in physiologic contexts where lipolysis is high. Moreover, knockdown or knockout of MGAT1 in adipocytes leads to higher rates of basal adipocyte lipolysis. Collectively, these data suggest that MGAT1 activity may play a role in regulating basal adipocyte FFA retention.

Nonalcoholic fatty liver disease (NAFLD) encompasses a range of liver pathology ranging from simple steatosis to varying degrees of inflammation, hepatocyte injury and fibrosis. Without intervention it can progress to end-stage liver disease and hepatocellular carcinoma. Given its close association with obesity, the prevalence of NAFLD has increased dramatically worldwide. Currently, there are no FDA-approved medications for the treatment of NAFLD and although lifestyle modifications with appropriate diet and exercise have been shown to be beneficial, this has been difficult to achieve and sustain for the majority of patients. As such, the search for effective therapeutic agents is an active area of research. Peroxisome proliferator-activated receptors (PPARs) belong to a class of nuclear receptors. Because of their key role in the transcriptional regulation of glucose and lipid metabolism, PPAR ligands have been investigated as possible therapeutic agents for NAFLD. Here we review the current evidence from preclinical and clinical studies investigating the therapeutic potential of PPAR ligands for the treatment of this spectrum of liver disorders.

Summary: Macrophage-mediated inflammation is critical in the pathogenesis of non-alcoholic steatohepatitis (NASH). Here, we describe that, with high-fat, high-sucrose-diet feeding, mature TIM4pos Kupffer cells (KCs) decrease in number, while monocyte-derived Tim4neg macrophages accumulate. In concert, monocyte-derived infiltrating macrophages enter the liver and consist of a transitional subset that expresses Cx3cr1/Ccr2 and a second subset characterized by expression of Trem2, Cd63, Cd9, and Gpmnb; markers ascribed to lipid-associated macrophages (LAMs). The Cx3cr1/Ccr2-expressing macrophages, referred to as C-LAMs, localize to macrophage aggregates and hepatic crown-like structures (hCLSs) in the steatotic liver. In C-motif chemokine receptor 2 (Ccr2)-deficient mice, C-LAMs fail to appear in the liver, and this prevents hCLS formation, reduces LAM numbers, and increases liver fibrosis. Taken together, our data reveal dynamic changes in liver macrophage subsets during the pathogenesis of NASH and link these shifts to pathologic tissue remodeling.